Aldosterone synthase inhibitors

ABSTRACT

The present invention relates to compounds of the formulas (IA) and (IB) and pharmaceutically acceptable salts thereof, wherein A and R 1 -R 6 , are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

FIELD OF THE INVENTION

This invention relates to heteroaryl compounds that are useful asinhibitors of aldosterone synthase (CYP11B2) and are thus useful fortreating a variety of diseases that are mediated or sustained byaldosterone activity, including renal disease, diabetic nephropathy,cardiovascular diseases and fibrotic disorders. This invention alsorelates to pharmaceutical compositions comprising these compounds,methods of using these compounds in the treatment of various diseasesand disorders, processes for preparing these compounds and intermediatesuseful in these processes.

BACKGROUND

Aldosterone is a steroid hormone having mineralcorticoid activity. It isproduced primarily by the adrenal glomerulosa in response to angiotensinII, adrenocorticotropic hormone and increased serum potassium levels. Aprimary physiological role of aldosterone in the kidney is to maintainsodium and potassium balance by regulating cation exchange (Na⁺reabsorption and K⁺ secretion) in the distal nephron. However,aldosterone has also been shown to be a pro-inflammatory and profibrotichormone in blood vessels, heart and kidneys. The effects of aldosteroneon gene expression are mediated via binding to the mineralocorticoidreceptor (MR) and a canonical nuclear hormone receptor pathway. However,the hormone also elicits rapid, non-genomic responses, including acuteregulation of the activity of tubular ion transporters, for exampleNa⁺/H⁺ exchangers (NHEs), H⁺-ATPase, ENaC, and Na⁺/K⁺ ATPase (D. W.Good, 2007, Hypertension, 49, 728-739). It is likely that some of theseeffects are mediated by MR-independent pathways. Conversely, the MR canbind alternative ligands, including deoxycorticosterone, corticosterone,cortisol and progesterone. Thus, inhibition of aldosterone synthesis ispredicted to have a pharmacodynamic profile distinct from what isobserved with MR antagonists.

Aldosterone is synthesized in the zona glomerulosa of the adrenalglands, where a single enzyme, CYP11B2 (aldosterone synthase), catalyzesthe 3-step conversion of 11-deoxycorticosterone (11-DOC) to aldosterone,via corticosterone and 18-hydroxycorticosterone. Adrenal aldosteronesynthase activity is regulated by Angiotensin II and K+ levels andunidentified adipocyte-derived mediators. Low levels of aldosteronesynthase have also been detected in the heart and CNS, though thephysiological relevance is uncertain, perhaps relating to paracrineeffects. Systemic aldosterone is believed to derive essentially entirelyfrom the adrenals.

Beyond its role in regulating sodium and potassium balance, aldosteronehas been shown to have pro-inflammatory and pro-fibrotic actions inmultiple tissues including the kidney, blood vessels and the heart. Theharmful effects of inappropriate aldosterone levels on blood pressureand cardiac, renal, cerebral and vascular function and structure, havebeen widely reported in the literature, including: i) increase in sodiumretention through Na⁺/K⁺ ATPase pump induction in distal tubulesresulting in volume expansion and high blood pressure, ii) endothelialdysfunction, iii) oxidative stress, iv) renal and cardiac hypertrophy,v) fibroblast proliferation, and, vi) excessive synthesis ofextracellular matrix resulting in renal, cardiac and vascular fibrosis.

Benefits of aldosterone blockade/inhibition include reduction of kidneyfibrosis and improvement of glomerular filtration rate and albuminuriain models of chronic kidney disease (CKD) and diabetic nephropathy. Thisis supported by pre-clinical data (for example, Fiebler et al., 2005,Circulation, 111, 3087-3094; Lea et al., 2009, Kidney International, 75,936-945). Other benefits reported in the literature include decreasedblood pressure and end-organ damage (heart, kidney, vessels) in bothrenin-dependent and salt-sensitive hypertension.

Although many of aldosterone's known effects are mediated throughmineralcorticoid receptor (MR) activation, and much of the evidencefavoring targeting this pathway comes from experiments with MRantagonists, non-MR mediated effects are reported and knockout mice forMR and aldosterone synthase exhibit different phenotypes (Makhanova etal. 2006, Berger et al. 1998, Funder 2007). These observations furthersuggest that aldosterone synthase inhibitors may have a differentprofile and offer advantages compared to MR antagonists.

For example, several aldosterone actions are not inhibited by MRantagonists, including the potentially deleterious effects on thevasculature (increased peripheral vascular resistance), the heart(effects on myocardial re-polarization) and the endocrine system(decreased insulin secretion). Furthermore, MR antagonism leads to anincrease in circulating aldosterone, predicted to increase aldosteronesignaling via non-MR pathways and, potentially, partially overcoming theMR blockade itself.

Current therapeutic strategies focus on slowing progression and treatingconditions underlying diabetic nephropathy: control of blood glucose andcontrol of high blood pressure. Angiotensin converting enzyme (ACE)inhibitors and angiotensin receptor blockers (ARB) have shown renalbenefit in diabetic patients. To date, representatives of the ACEinhibitor class and from the ARB class have been approved for thetreatment of diabetic nephropathy. These therapies represent limitedbenefit for the diabetic nephropathy patients.

Although the use of ACE inhibitors and ARBs represents the currentstandard of care for patients with diabetic nephropathy, patientsprogressively lose kidney function while on these medications, as seenin the IDNT (E. J. Lewis et al., 2001, N. Engl. J. Med., 345, 851-860)and RENAAL (B. M. Brenner et al., 2001, N. Engl. J. Med., 345, 861-869)studies, which reported a decrease over time in estimated glomerularfiltration rate, which is an accurate measure of chronic kidney diseaseprogression in patients treated by these conventional methods. At stage5 chronic kidney disease, renal replacement therapy is required, in theform of either dialysis or transplant.

Aldosterone synthase inhibition may also be predicted to offeradvantages as add-on therapy with ACE inhibitors and ARBs. Notably,25-50% of patients receiving these agents experience “aldosteronebreakthrough” in which aldosterone levels initially lowered by thesetreatments eventually return to pretreatment levels. This phenomenonwould not occur with direct aldosterone synthase inhibition and couldenhance efficacy in combination therapy.

There remains a high unmet medical need to treat diabetic nephropathy,to halt or regress disease progression by specifically targeting theunderlying pathophysiological mechanisms associated with chronicinflammation and fibrosis, irrespective of the original cause of thedisease and when co-administered with current therapies. The studiesdescribed above and in the literature provide evidence that inhibitorsof aldosterone synthesis will be useful for the treatment of diabetickidney disease including diabetic nephropathy; non-diabetic kidneydisease including glomerulosclerosis, glomerulonephritis, IGAnephropathy, nephritic syndrome and focal segmental glomerulosclerosis(FSGS); cardiovascular diseases including hypertension, pulmonaryarterial hypertension, Conn's syndrome, systolic heart failure,diastolic heart failure, left ventricular dysfunction, left ventricularstiffness and fibrosis, left ventricular filing abnormalities, arterialstiffness, atherosclerosis and cardiovascular morbidity associated withprimary or secondary hyperaldosteronism; adrenal hyperplasia and primaryand secondary hyperaldosteronism.

BRIEF SUMMARY OF THE INVENTION

The present invention provides novel compounds that inhibit aldosteronesynthase and thus useful for treating a variety of diseases anddisorders that can be alleviated by lowering levels of aldosteroneincluding renal disease, diabetic nephropathy, cardiovascular diseasesand fibrotic disorders. This invention also relates to pharmaceuticalcompositions comprising these compounds, methods of using thesecompounds in the treatment of various diseases and disorders, processesfor preparing these compounds and intermediates useful in theseprocesses.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment of the invention, there are provided compounds of theformulas IA or IB

wherein:

A is selected from the group consisting of

benzoimidazolyl, benzo[d]isoxazolyl, benzooxazolyl, benzothiazolyl,benzotriazolyl, chromanyl, chromenyl, cyclohexen-1-yl,2,3-dihydro-benzo[1,4]dioxinyl, 2,3-dihydro-5H-benzo[e][1,4]dioxepinyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-onyl, 2,3-dihydro-benzofuranyl,4,5-dihydro-1H-indazolyl, 1,3-dihydroindol-2-onyl,1,3-dihydro-isoindolyl, 3,4-dihydro-2H-isoquinolin-1-onyl,3,4-dihydro-2H-naphthalen-1-onyl, 3,4-dihydro-2H-[1,8]napthyridinyl,7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, 6,7-dihydro-[1]pyrindin-5-onyl,3,4-dihydro-1H-quinolin-2-onyl, imidazo[1,2-a]pyridinyl,imidazo[1,5-a]pyridinyl, indanyl, indazolyl, indolyl, isochromanyl,isoquinolinyl, phenyl, pyrazolyl, pyrrolo[2,3-b]pyridinyl, quinolinyl,1,3,4,5-tetrahydro-benzo[c]oxepinyl, 4, 5, 6, 7-tetrahydroindazolyl,thiazolyl and [1,2,4]triazolo[4,3-a]pyridinyl;

wherein A is optionally substituted with one to three groups selectedfrom C₁₋₆alkyl, C₃₋₅cycloalkyl, —OH, oxo, C₁₋₆alkoxy, halogen, —CF₃,—CN, —C(O)C₁₋₃alkyl and —C(O)NH₂;

R¹ is selected from H and —C₁₋₃alkyl;

R² is selected from —OH, —CN, —NH₂, —N(C₁₋₃alkyl)₂, —NHC(O)C₁₋₃alkyl,—NHC(O) C₃₋₅ cycloalkyl, —NHSO₂C₁₋₃alkyl and —NHC(O)CH₂C(CH₃)₂—OH;

R³ is H;

R⁴ is H; or

R³ and R⁴ together form a Spiro cyclopropyl group;

R⁵ is H or —C₁₋₃alkyl; and

R⁶ is —OH;

or a salt thereof.

In another embodiment there are provided compounds of the formula IAaccording to the embodiment above, wherein A, R¹, R² R³ and R⁴ are asdefined in the embodiment above;

or a salt thereof.

In another embodiment there are provided compounds of the formula IBaccording to the first embodiment, wherein

A is selected from the group consisting of

benzo[d]isoxazol-5-yl, benzotriazol-5-yl, chromen-6- or -7-yl,cyclohexen-1-yl, 4,5-dihydro-1H-indazol-6-yl,3,4-dihydro-2H-[1,8]napthyridin-6-yl, imidazo[1,5-a]pyridine-6-yl,indan-5-yl, indazol-5- or -6-yl, isochroman-7-yl,2,3-dihydro-benzo[1,4]dioxin-6-yl,3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl,2,3-dihydro-5H-benzo[e][1,4]dioxepin-7-yl,3,4-dihydro-2H-naphthalen-1-on-6- or -7-yl, chroman-6- or -7-yl,1,3,4,5-tetrahydro-benzo[c]oxepin-8-yl and 4, 5, 6,7-tetrahydroindazol-6-yl;

R⁵ is H or —CH₃; and

R⁶ is OH;

or a salt thereof.

In another embodiment there are provided compounds of the formula IAaccording to the first or second embodiment, wherein

A is selected from the group consisting of

benzoimidazol-5-yl, benzo[d]isoxazol-5-yl, benzooxazol-5-yl,benzothiazol-5-yl, benzotriazol-5-yl, chroman-6- or -7-yl, chromen-6- or-7-yl, cyclohexen-1-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl,2,3-dihydro-5H-benzo[e][1,4]dioxepin-7-yl,3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, 4,5-dihydro-1H-indazol-6-yl,1,3-dihydroindol-2-on-5-yl, 3,4-dihydro-2H-isoquinolin-1-on-6-yl,3,4-dihydro-2H-naphthalen-1-on-6- or -7-yl,3,4-dihydro-2H-[1,8]napthyridin-6-yl, 3,4-dihydro-1H-quinolin-2-on-6-yl,imidazo[1,2-a]pyridine-7-yl, imidazo[1,5-a]pyridine-6-yl, indan-5-yl,indazol-5- or -6-yl, isochroman-7-yl, isoquinolin-6-yl, phenyl,quinolin-3- or -6-yl and 4, 5, 6, 7-tetrahydroindazol-6-yl, indol-5 or6-yl, 1,3,4,5-tetrahydro-benzo[c]oxepin-8-yl;

wherein A is optionally substituted with one to three groups selectedfrom C₁₋₃alkyl, C₃₋₅cycloalkyl, —OH, oxo, C₁₋₃alkoxy, Cl, F, —CF₃, —CN,—C(O)CH₃ and —C(O)NH₂;

R¹ is selected from H and —CH₃;

R² is selected from —OH, —CN, —NH₂, —N(CH₃)₂, —NHC(O)C₁₋₃alkyl,—NHC(O)cyclopropyl, —NHSO₂C₁₋₃alkyl and —NHC(O)CH₂C(CH₃)₂—OH;

or a salt thereof.

In another embodiment there are provided compounds of the formula IAaccording to the first, second or fourth embodiment, wherein

A is selected from the group consisting of

benzo[d]isoxazol-5-yl, benzotriazol-5-yl, chromen-6- or -7-yl,cyclohexen-1-yl, 4,5-dihydro-1H-indazol-6-yl,3,4-dihydro-2H-[1,8]napthyridin-6-yl, imidazo[1,5-a]pyridine-6-yl,indan-5-yl, indazol-5- or -6-yl, isochroman-7-yl,2,3-dihydro-benzo[1,4]dioxin-6-yl,3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl,2,3-dihydro-5H-benzo[e][1,4]dioxepin-7-yl,3,4-dihydro-2H-naphthalen-1-on-6- or -7-yl, chroman-6- or -7-yl,1,3,4,5-tetrahydro-benzo[c]oxepin-8-yl and 4, 5, 6,7-tetrahydroindazol-6-yl;

wherein A is optionally substituted with one to three groups selectedfrom C₁₋₃alkyl, C₃₋₅cycloalkyl, —OH, oxo, C₁₋₃alkoxy, Cl, F, —CF₃, —CN,—C(O)CH₃ and —C(O)NH₂; and

R² is selected from —OH, —CN, —NHC(O)C₁₋₃alkyl, —NHC(O)cyclopropyl,—NHSO₂C₁₋₃alkyl and —NHC(O)CH₂C(CH₃)₂—OH;

or a salt thereof.

In another aspect of the invention, there is provided a compound of thegeneral formula I or a pharmaceutically acceptable salt thereof for usein a therapeutic method as described hereinbefore and hereinafter.

Table 1 shows representative compounds of the invention which can bemade by the methods described in the general synthetic schemes, theexamples, and known methods in the art.

TABLE 1 Cpd No STRUCTURE Name 1

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-3,4-dihydro-1H-quinolin-2-one, Enantiomer II 2

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-3,4-dihydro-1H-quinolin-2-one, Enantiomer I 3

8-Phenyl-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol, Enantiomer I 4

4-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)- benzonitrile,Enantiomer I 5

8-Phenyl-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol, Enantiomer II 6

4-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)- benzonitrile,Enantiomer II 7

2-Chloro-4-(4-hydroxy-3,4-dihydro- 1H-pyrano[4,3-c]pyridin-8-yl)-benzonitrile, Enantiomer I 8

8-(2-Isopropoxy-thiazol-4-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer I 9

8-(1-Methyl-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridine-4-carbonitrile 10

8-(3-Methyl-1H-indazol-5-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4- ol,Enantiomer I 11

8-(3-Methyl-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4- ol,Enantiomer I 12

8-(3-Methyl-1H-indazol-5-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4- ol,Enantiomer II 13

8-(3-Methyl-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4- ol,Enantiomer II 14

8-(3-Methyl-3H-benzotriazol-5-yl)- 3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 15

8-(3-Fluoro-1-methyl-1H-indazol-6- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 16

8-(1-methylindazol-6-yl)spiro[1,4- dihydropyrano[4,3-c]pyridine-3,1′-cyclopropane]-4-ol, Enantiomer I 17

8-(1-methylindazol-6-yl)spiro[1,4- dihydropyrano[4,3-c]pyridine-3,1′-cyclopropane]-4-ol, Enantiomer II 18

8-(5-Fluoro-1-methyl-1H-indazol-6- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 19

8-(5-Fluoro-1-methyl-1H-indazol-6- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer I 20

8-Benzothiazol-5-yl-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol,Enantiomer I 21

8-(1H-Indol-6-yl)-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol, EnantiomerI 22

8-Quinolin-6-yl-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol, Enantiomer I23

8-(1-Methyl-1H-indazol-5-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4- ol,Enantiomer I 24

8-(1H-Indazol-6-yl)-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol,Enantiomer I 25

8-(2,3-Dihydro-benzo[1,4]dioxin-6- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer I 26

8-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin- 4-ol, Enantiomer I 27

8-(1H-Pyrrolo[2,3-b]pyridin-5-yl)- 3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer I 28

8-(3,4-Dihydro-2H- benzo[b][1,4]dioxepin-7-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4- ol, Enantiomer I 29

8-(1-Methyl-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4- ol,Enantiomer I 30

8-Isoquinolin-6-yl-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol, EnantiomerI 31

8-(1H-Indol-5-yl)-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol, EnantiomerI 32

8-(1-Methyl-1H-pyrazol-4-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4- ol,Enantiomer II 33

8-Benzothiazol-5-yl-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol,Enantiomer II 34

8-(1H-Indol-6-yl)-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol, EnantiomerII 35

8-Quinolin-6-yl-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol, Enantiomer II36

8-(1-Methyl-1H-indazol-5-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4- ol,Enantiomer II 37

8-(1H-Indazol-6-yl)-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol,Enantiomer II 38

8-(2,3-Dihydro-benzo[1,4]dioxin-6- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 39

8-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin- 4-ol, Enantiomer II 40

8-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 41

8-(1,5-Dimethyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 42

8-(2-Methyl-5-trifluoromethyl-2H- pyrazol-3-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 43

8-(3,4-Dihydro-2H- benzo[b][1,4]dioxepin-7-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4- ol, Enantiomer II 44

8-(1-Methyl-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4- ol,Enantiomer II 45

8-Isoquinolin-6-yl-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol, EnantiomerII 46

8-(1-Cyclopropyl-1H-pyrazol-4-yl)- 3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 47

8-(1H-Indazol-5-yl)-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol,Enantiomer II 48

8-(1H-Indol-5-yl)-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol, EnantiomerII 49

8-Benzooxazol-5-yl-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol, EnantiomerII 50

8-(2-Methyl-2H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4- ol,Enantiomer II 51

5-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-1-methyl-1,3-dihydro-indol-2-one, Enantiomer II 52

5-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-1,3-dihydro-indol-2-one, Enantiomer II 53

8-Benzooxazol-5-yl-3,4-dihydro-1H- pyrano[4,3-c]pyridin-4-ol, EnantiomerI 54

5-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-1-methyl-1,3-dihydro-indol-2-one, Enantiomer I 55

8-(3-Fluoro-1-methyl-1H-indazol-6- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer I 56

N-(8-Benzooxazol-5-yl-3,4-dihydro- 1H-pyrano[4,3-c]pyridin-4-yl)-propionamide, Enantiomer II 57

N-[8-(3-Methyl-3H-benzoimidazol- 5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide, Enantiomer II 58

N-[8-(1-Methyl-2-oxo-2,3-dihydro- 1H-indol-5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]- propionamide, Enantiomer II 59

N-[8-(2-Oxo-2,3-dihydro-1H-indol-5- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide, Enantiomer II 60

N-[8-(3-Methyl-3H-benzotriazol-5- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide, Enantiomer II 61

N-[8-(3-Methyl-1H-indazol-5-yl)- 3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide, Enantiomer II 62

N-[8-(3-Methyl-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide, Enantiomer II 63

Ethanesulfonic acid [8-(1-methyl-2- oxo-2,3-dihydro-1H-indol-5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4- yl]-amide, Enantiomer II 64

Ethanesulfonic acid [8-(2-oxo-2,3- dihydro-1H-indol-5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 65

Ethanesulfonic acid [8-(3-methyl-3H- benzotriazol-5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 66

Ethanesulfonic acid [8-(3-methyl-1H- indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 67

Ethanesulfonic acid [8-(3-methyl-3H- benzoimidazol-5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 68

Ethanesulfonic acid [8-(3-fluoro-1- methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 69

Ethanesulfonic acid [8-(3-methyl-1H- indazol-5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 70

8-(1,5-Dimethyl-1H-indazol-6-yl)- 3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ylamine, Enantiomer II 71

8-(1-Methyl-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-ylamine, Enantiomer II 72

N-[8-(1-Methyl-1H-indazol-5-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide, Enantiomer I 73

N-[8-(1-Methyl-1H-indazol-5-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide, Enantiomer II 74

N-[8-(1-Methyl-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-acetamide, Enantiomer II 75

Cyclopropanecarboxylic acid [8-(1- methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 76

N-[8-(1-Methyl-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide, Enantiomer II 77

N-[8-(1-Methyl-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-isobutyramide, Enantiomer II 78

Ethanesulfonic acid [8-(1,5-dimethyl- 1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer I 79

Ethanesulfonic acid [8-(1,5-dimethyl- 1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 80

N-[8-(1-Methyl-1H-indazol-6-yl)- 3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-methanesulfonamide, Enantiomer I 81

N-[8-(1-Methyl-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-methanesulfonamide, Enantiomer II 82

Ethanesulfonic acid [8-(1-methyl-1H- indazol-5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 83

Ethanesulfonic acid [8-(1-methyl-1H- indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 84

6-[4-hydroxyspiro[1,4- dihydropyrano[4,3-c]pyridine-3,1′-cyclopropane]-8-yl]-3,4-dihydro-2H- isoquinolin-1-one, Enantiomer I 85

6-[4-hydroxyspiro[1,4- dihydropyrano[4,3-c]pyridine-3,1′-cyclopropane]-8-yl]-3,4-dihydro-2H- isoquinolin-1-one, Enantiomer II 86

8-(3-Methyl-imidazo[1,5-a]pyridin-6- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer I 87

8-(3-Methyl-imidazo[1,5-a]pyridin-6- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 88

8-(3-methylimidazo[1,5-a]pyridin-6- yl)spiro[1,4-dihydropyrano[4,3-c]pyridine-3,1′-cyclopropane]-4-ol, Enantiomer I 89

8-(3-methylimidazo[1,5-a]pyridin-6- yl)spiro[1,4-dihydropyrano[4,3-c]pyridine-3,1′-cyclopropane]-4-ol, Enantiomer II 90

8-(3-Methyl-benzo[d]isoxazol-5-yl)- 3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 91

8-(3-methyl-[1,2,4]triazolo[4,3- a]pyridin-6-yl)spiro[1,4-dihydropyrano[4,3-c]pyridine-3,1′- cyclopropane]-4-ol, Enantiomer I 92

8-(4-fluoro-1-methyl-indazol-6- yl)spiro[1,4-dihydropyrano[4,3-c]pyridine-3,1′-cyclopropane]-4-ol, Enantiomer II 93

8-(3-methyl-[1,2,4]triazolo[4,3- a]pyridin-6-yl)spiro[1,4-dihydropyrano[4,3-c]pyridine-3,1′- cyclopropane]-4-ol, Enantiomer II 94

8-(3-Methyl-benzo[d]isoxazol-5-yl)- 3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer I 95

8-(3-Methyl-[1,2,4]triazolo[4,3- a]pyridin-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer I 96

8-(4-Fluoro-1-methyl-1H-indazol-6- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 97

8-(3-Methyl-[1,2,4]triazolo[4,3- a]pyridin-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 98

8-[1,2,4]Triazolo[4,3-a]pyridin-6-yl-3,4-dihydro-1H-pyrano[4,3-c]pyridin- 4-ol, Enantiomer II 99

8-Imidazo[1,2-a]pyridin-7-yl-3,4- dihydro-1H-pyrano[4,3-c]pyridin- 4-ol,Enantiomer I 100

8-[1,2,4]Triazolo[4,3-a]pyridin-6-yl-3,4-dihydro-1H-pyrano[4,3-c]pyridin- 4-ol, Enantiomer I 101

8-Imidazo[1,2-a]pyridin-7-yl-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4- ol,Enantiomer II 102

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1- carboxylic acid amide 103

5-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-indan-1- one,Enantiomer II 104

3-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-quinoline-8-carboxylic acid amide, Enantiomer I 105

3-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-quinoline-8-carboxylic acid amide, Enantiomer II 106

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-1-methyl-1H-indazole-4-carbonitrile, Enantiomer II 107

8-(2,3-Dihydro-5H- benzo[e][1,4]dioxepin-7-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin- 4-ol, Enantiomer II 108

8-(2,3-Dihydro-5H- benzo[e][1,4]dioxepin-7-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4- ol, Enantiomer I 109

1-[5-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-1,3-dihydro-isoindol-2-yl]-ethanone, Enantiomer II 110

7-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-chromen- 4-one,Enantiomer II 111

8-(3,5-dihydro-2H-1,4- benzo[e][1,4]dioxepin-7-yl)spiro[1,4-dihydropyrano[4,3- c]pyridine-3,1′-cyclopropane]- 4-ol,Enantiomer I 112

8-(3,5-dihydro-2H-1,4- benzo[e][1,4]dioxepin-7-yl)spiro[1,4-dihydropyrano[4,3-c]pyridine-3,1′- cyclopropane]-4-ol, Enantiomer II 113

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-1-methyl-1H-indazole-3-carbonitrile, Enantiomer II 114

8-(3-methyl-1,2-benzoxazol-5- yl)spiro[1,4-dihydropyrano[4,3-c]pyridine-3,1′-cyclopropane]-4-ol, Enantiomer II 115

7-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-3,4-dihydro-2H-naphthalen-1-one, Enantiomer I 116

7-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-3,4-dihydro-2H-naphthalen-1-one, Enantiomer II 117

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-3,4-dihydro-2H-naphthalen-1-one, Enantiomer I 118

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-3,4-dihydro-2H-naphthalen-1-one, Enantiomer II 119

7-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-3,4-dihydro-2H-isoquinolin-1-one, Enantiomer II 120

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-3,4-dihydro-2H-isoquinolin-1-one, Enantiomer I 121

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-3,4-dihydro-2H-isoquinolin-1-one, Enantiomer II 122

7-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-chroman- 4-one,Enantiomer I 123

7-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-chroman- 4-one,Enantiomer II 124

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-2-methyl-3,4-dihydro-2H-isoquinolin-1-one, Enantiomer II 125

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-chromen- 2-one,Enantiomer I 126

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-chromen- 2-one,Enantiomer II 127

8-(3-Chloro-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4- ol,Enantiomer II 128

N-[8-(3-Chloro-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide, Enantiomer II 129

Ethanesulfonic acid [8-(3-chloro-1H- indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 130

8-(4-Chloro-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4- ol,Enantiomer I 131

8-(4-Hydroxy-chroman-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4- ol,Stereoisomer I 132

N-[8-(4-Hydroxy-chroman-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide, Stereoisomer I 133

Ethanesulfonic acid [8-(4-hydroxy- chroman-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Stereoisomer I 134

8-(4-Hydroxy-chroman-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4- ol,Stereoisomer II 135

N-[8-(4-Hydroxy-chroman-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide, Stereoisomer II 136

Ethanesulfonic acid [8-(4-hydroxy- chroman-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Stereoisomer II 137

8-(4-Hydroxy-4-methyl-chroman-6- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Stereoisomer I 138

8-(4-Hydroxy-4-methyl-chroman-6- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Stereoisomer II 139

8-(4-Hydroxy-4-methyl-chroman-6- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Stereoisomer III 140

8-(4-Hydroxy-4-methyl-chroman-6- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Stereoisomer IV 141

8-(4,4-Difluoro-chroman-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-ol,Enantiomer II 142

8-(4,4-Difluoro-chroman-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-ol,Enantiomer I 143

N-[8-(4,4-Difluoro-chroman-6-yl)- 3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide, Enantiomer II 144

Ethanesulfonic acid [8-(4,4-difluoro- chroman-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 145

8-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5- one, Enantiomer II 146

8-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5- one, Enantiomer I 147

N-[8-(5-Oxo-2,3,4,5-tetrahydro- benzo[f][1,4]oxazepin-8-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4- yl]-propionamide, Enantiomer II 148

8-(5,5-Difluoro-1,3,4,5-tetrahydro- benzo[c]oxepin-8-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 149

8-(4-Fluoro-1-methyl-1H-indazol-6- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ylamine, Enantiomer II 150

N-[8-(4-Fluoro-1-methyl-1H-indazol- 6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide, Enantiomer II 151

N-[8-(1-Oxo-indan-5-yl)-3,4-dihydro- 1H-pyrano[4,3-c]pyridin-4-yl]-acetamide, Enantiomer I 152

N-[8-(1-Oxo-indan-5-yl)-3,4-dihydro- 1H-pyrano[4,3-c]pyridin-4-yl]-acetamide, Enantiomer II 153

3-Hydroxy-3-methyl-N-[8-(1-oxo- indan-5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]- butyramide, Enantiomer II 154

N-[8-(2-Oxo-2H-chromen-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-acetamide, Enantiomer II 155

N-[8-(1-Methyl-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide, Enantiomer I 156

N-[8-(3-Methyl-benzo[d]isoxazol-5- yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]- propionamide, Enantiomer I 157

Ethanesulfonic acid [8-(1-oxo-indan- 5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 158

Ethanesulfonic acid [8-(2-oxo-2H- chromen-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 159

Ethanesulfonic acid [8-(3-methyl- benzo[d]isoxazol-5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer I 160

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[3,4-c]pyridin-5-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1- carboxylic acid amide 161

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[3,4-c]pyridin-5-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1- carboxylic acid amide, Enantiomer I 162

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[3,4-c]pyridin-5-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1- carboxylic acid amide, Enantiomer II163

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1- carboxylic acid amide, Enantiomer I 164

6-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1- carboxylic acid amide, Enantiomer II165

5-(1-Methyl-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[3,4-c]pyridin-4- ol,Enantiomer II 166

5-(1-Methyl-1H-indazol-6-yl)-3,4- dihydro-1H-pyrano[3,4-c]pyridin-4- ol,Enantiomer I 167

5-Isoquinolin-6-yl-3,4-dihydro-1H- pyrano[3,4-c]pyridin-4-ol, EnantiomerII 168

5-Isoquinolin-6-yl-3,4-dihydro-1H- pyrano[3,4-c]pyridin-4-ol, EnantiomerI 169

4-Methyl-8-(1-methyl-1H-indazol- 6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 170

4-Methyl-8-(1-methyl-1H-indazol- 6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer I 171

8-(3-Fluoro-1-methyl-1H-indazol-6- yl)-4-methyl-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer I 172

8-(3-Fluoro-1-methyl-1H-indazol-6- yl)-4-methyl-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 173

6-(4-Hydroxy-4-methyl-3,4-dihydro- 1H-pyrano[4,3-c]pyridin-8-yl)-1-methyl-1H-indazole-4-carbonitrile, Enantiomer I 174

6-(4-Hydroxy-4-methyl-3,4-dihydro- 1H-pyrano[4,3-c]pyridin-8-yl)-1-methyl-1H-indazole-4-carbonitrile, Enantiomer II 175

8-(4-Fluoro-1-methyl-1H-indazol-6- yl)-4-methyl-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 176

8-(4-Fluoro-1-methyl-1H-indazol-6- yl)-4-methyl-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer I 177

6-(4-Hydroxy-4-methyl-3,4-dihydro- 1H-pyrano[4,3-c]pyridin-8-yl)-1-methyl-1H-indazole-3-carbonitrile, Enantiomer I 178

6-(4-Hydroxy-4-methyl-3,4-dihydro- 1H-pyrano[4,3-c]pyridin-8-yl)-1-methyl-1H-indazole-3-carbonitrile, Enantiomer II 179

4-Methyl-5-(1-methyl-1H-indazol- 6-yl)-3,4-dihydro-1H-pyrano[3,4-c]pyridin-4-ol, Enantiomer II 180

4-Methyl-5-(1-methyl-1H-indazol-6- yl)-3,4-dihydro-1H-pyrano[3,4-c]pyridin-4-ol, Enantiomer I 181

2-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-6,7-dihydro-[1]pyrindin-5-one, Enantiomer I 182

8-(3,3-Dimethyl-2,3-dihydro- benzofuran-5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer I 183

5-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-indan- 1-one,Enantiomer I 184

Ethanesulfonic acid [8-(1-hydroxy- indan-5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, mixture of diastereomers 185

Dimethyl-[8-(1-methyl-1H-indazol- 6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amine, Enantiomer II 186

4-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-cyclohex-3-enecarbonitrile, Enantiomer I 187

8-(1-Methyl-4,5-dihydro-1H-indazol- 6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 188

8-(3-Methyl-3H-benzotriazol-5-yl)- 3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer I 189

8-(1-Methyl-4,5-dihydro-1H-indazol- 6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer I 190

8-(1-Methyl-4,5,6,7-tetrahydro-1H- indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Diastereomer I 191

8-(1-Methyl-4,5,6,7-tetrahydro-1H- indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Diastereomer II 192

4-(4-Hydroxy-3,4-dihydro-1H- pyrano[4,3-c]pyridin-8-yl)-cyclohex-3-enecarbonitrile, Enantiomer II 193

N-[8-(5-Fluoro-1-methyl-1H-indazol- 6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide, Enantiomer II 194

N-[8-(4,4-Difluoro-isochroman-7-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin- 4-yl]-propionamide, Enantiomer II195

Ethanesulfonic acid [8-(5-fluoro-1- methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 196

Ethanesulfonic acid [8-(4,4-difluoro- isochroman-7-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide, Enantiomer II 197

8-(3-methylbenzotriazol-5- yl)spiro[1,4-dihydropyrano[4,3-c]pyridine-3,1′-cyclopropane]-4-ol, Enantiomer I 198

8-(3-methylbenzotriazol-5- yl)spiro[1,4-dihydropyrano[4,3-c]pyridine-3,1′-cyclopropane]-4-ol, Enantiomer II 199

8-(4,4-Difluoro-isochroman-7-yl)- 3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer II 200

8-(4,4-Difluoro-isochroman-7-yl)- 3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol, Enantiomer I

In one embodiment, the invention relates to a compound selected from thegroup consisting of compounds 1-200 depicted in Table 1 above and thepharmaceutically acceptable salts thereof.

In another embodiment, the invention relates to compounds 1, 4-7, 9,12-18, 22, 29, 30, 33-38, 43-45, 47-49, 51, 52, 55, 56, 60, 61, 65, 68,69, 71, 73-77, 81, 83, 85, 89, 90, 92, 94, 96, 102-105, 107, 110,112-114, 116, 118, 121, 123, 125-129, 131-133, 136, 142, 143, 148-150,152-154, 157, 158, 160-164, 166, 168-172, 175-179, 183, 185-199 depictedin Table 1 above and the pharmaceutically acceptable salts thereof.

In another embodiment, the invention relates to compounds 9, 12-18, 29,34, 36-38, 43-45, 47, 48, 55, 60, 61, 65, 68, 69, 71, 73-77, 81, 83, 85,89, 90, 92, 94, 96, 102-105, 107, 110, 112-114, 116, 118, 121, 123,125-129, 131-133, 136, 142, 143, 148-150, 152-154, 157, 158, 160-164,166, 168-172, 175-179, 183 and 185-199 depicted in Table 1 above and thepharmaceutically acceptable salts thereof.

In another embodiment, the invention relates to compounds 1-159, 163,164, 169-178, and 181-199.

In another embodiment, the invention relates to compounds 160-162,165-168 and 179-180.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof aswell as mixtures in different proportions of the separate enantiomers,mixtures of diastereomers, or mixtures of any of the foregoing formswhere such isomers and enantiomers exist, as well as salts, includingpharmaceutically acceptable salts thereof and solvates thereof such asfor instance hydrates including solvates of the free compounds orsolvates of a salt of the compound.

Some of the compounds of formula (I) can exist in more than onetautomeric form. The invention includes methods for using all suchtautomers.

Compounds of the invention also include their isotopically-labelledforms. An isotopically-labelled form of an active agent of a combinationof the present invention is identical to said active agent but for thefact that one or more atoms of said active agent have been replaced byan atom or atoms having an atomic mass or mass number different from theatomic mass or mass number of said atom which is usually found innature. Examples of isotopes which are readily available commerciallyand which can be incorporated into an active agent of a combination ofthe present invention in accordance with well established procedures,include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S, ¹⁸F, ³⁶Cl, respectively. An active agent of a combination of thepresent invention, a prodrug thereof, or a pharmaceutically acceptablesalt of either which contains one or more of the above-mentionedisotopes and/or other isotopes of other atoms is contemplated to bewithin the scope of the present invention.

The invention includes pharmaceutically acceptable derivatives ofcompounds of formula (I). A “pharmaceutically acceptable derivative”refers to any pharmaceutically acceptable salt or ester, or any othercompound which, upon administration to a patient, is capable ofproviding (directly or indirectly) a compound useful for the invention,or a pharmacologically active metabolite or pharmacologically activeresidue thereof. A pharmacologically active metabolite shall beunderstood to mean any compound of the invention capable of beingmetabolized enzymatically or chemically. This includes, for example,hydroxylated or oxidized derivative compounds of the formula (I).

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. For example,such salts include acetates, ascorbates, benzenesulfonates, benzoates,besylates, bicarbonates, bitartrates, bromides/hydrobromides, edetates,camsylates, carbonates, chlorides/hydrochlorides, citrates, edisylates,ethane disulfonates, estolates, esylates, fumarates, gluceptates,gluconates, glutamates, glycolates, glycollylarsnilates,hexylresorcinates, hydrabamines, hydroxymaleates, hydroxynaphthoates,iodides, isothionates, lactates, lactobionates, malates, maleates,mandelates, methanesulfonates, methylbromides, methylnitrates,methylsulfates, mucates, napsylates, nitrates, oxalates, pamoates,pantothenates, phenylacetates, phosphates/diphosphates,polygalacturonates, propionates, salicylates, stearates, subacetates,succinates, sulfamides, sulfates, tannates, tartrates, teoclates,toluenesulfonates, triethiodides, ammonium, benzathines,chloroprocaines, cholines, diethanolamines, ethylenediamines, megluminesand procaines. Further pharmaceutically acceptable salts can be formedwith cations from metals like aluminium, calcium, lithium, magnesium,potassium, sodium, zinc and the like. (also see Pharmaceutical salts,Birge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts) also comprise a part of the invention.

In addition, within the scope of the invention is use of prodrugs ofcompounds of the formula (I). Prodrugs include those compounds that,upon simple chemical transformation, are modified to produce compoundsof the invention. Simple chemical transformations include hydrolysis,oxidation and reduction. Specifically, when a prodrug is administered toa patient, the prodrug may be transformed into a compound disclosedhereinabove, thereby imparting the desired pharmacological effect.

The compounds of the invention are only those which are contemplated tobe ‘chemically stable’ as will be appreciated by those skilled in theart. For example, peroxides or a compound which would have a ‘danglingvalency’, or a ‘carbanion’ are not compounds contemplated by theinventive methods disclosed herein.

For all compounds disclosed hereinabove in this application, in theevent the nomenclature is in conflict with the structure, it shall beunderstood that the compound is defined by the structure.

All terms as used herein in this specification, unless otherwise stated,shall be understood in their ordinary meaning as known in the art. Forexample, “C₁₋₄alkyl” is a saturated aliphatic hydrocarbon monovalentradical containing 1-4 carbons such as methyl, ethyl, n-propyl,1-methylethyl (isopropyl), n-butyl or t-butyl; “C₁₋₄ alkoxy” is a C₁₋₄alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, butoxy.All alkyl, alkenyl and alkynyl groups shall be understood as beingbranched or unbranched, cyclized or uncyclized where structurallypossible and unless otherwise specified. Other more specific definitionsare as follows:

The term “C_(1-n)-alkyl”, wherein n is an integer from 2 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer 1 to n, either aloneor in combination with another radical, denotes an acyclic, straight orbranched chain divalent alkyl radical containing from 1 to n carbonatoms. For example the term C₁₋₄-alkylene includes —(CH₂)—, —(CH₂—CH₂)—,—(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer 4 to n, eitheralone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Forexample the term C₃₋₇-cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

The term “heteroatom” as used herein shall be understood to mean atomsother than carbon such as O, N, S and P.

In all alkyl groups or carbon chains one or more carbon atoms can beoptionally replaced by heteroatoms: O, S or N, it shall be understoodthat if N is not substituted then it is NH, it shall also be understoodthat the heteroatoms may replace either terminal carbon atoms orinternal carbon atoms within a branched or unbranched carbon chain. Suchgroups can be substituted as herein above described by groups such asoxo to result in definitions such as but not limited to: alkoxycarbonyl,acyl, amido and thioxo.

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may be further fused to a second 5- or6-membered carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl anddihydronaphthyl.

The term “heteroaryl” means an aromatic 5 to 6-membered monocyclicheteroaryl or an aromatic 7 to 11-membered heteroaryl bicyclic ringwhere at least one of the rings is aromatic, wherein the heteroaryl ringcontains 1-4 heteroatoms such as N, O and S. Non-limiting examples of 5to 6-membered monocyclic heteroaryl rings include furanyl, oxazolyl,isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl,tetrazolyl, triazolyl, thienyl, thiadiazolyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazinyl, and purinyl. Non-limiting examples of7 to 11-membered heteroaryl bicyclic heteroaryl rings includebenzimidazolyl, quinolinyl, dihydro-2H-quinolinyl, tetrahydroquinolinyl,isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl,indolyl, isoindolyl, benzofuranyl, dihydrobenzofuranyl, benzopyranyl,benzodioxolyl, benzoxazolyl and benzothiazolyl.

The term “heterocyclyl” means a stable nonaromatic 4-8 memberedmonocyclic heterocyclic radical or a stable nonaromatic 6 to 11-memberedfused bicyclic, bridged bicyclic or spirocyclic heterocyclic radical.The 5 to 11-membered heterocycle consists of carbon atoms and one ormore, preferably from one to four heteroatoms chosen from nitrogen,oxygen and sulfur. The heterocycle may be either saturated or partiallyunsaturated. Non-limiting examples of nonaromatic 4-8 memberedmonocyclic heterocyclic radicals include tetrahydrofuranyl, azetidinyl,pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl,and azepinyl. Non-limiting examples of nonaromatic 6 to 11-memberedfused bicyclic radicals include octahydroindolyl, octahydrobenzofuranyl,and octahydrobenzothiophenyl. Non-limiting examples of nonaromatic 6 to11-membered bridged bicyclic radicals include2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, and3-azabicyclo[3.2.1]octanyl. Non-limiting examples of nonaromatic 6 to11-membered spirocyclic heterocyclic radicals include7-aza-spiro[3,3]heptanyl, 7-spiro[3,4]octanyl, and7-aza-spiro[3,4]octanyl. The term “heterocyclyl” or is intended toinclude all the possible isomeric forms.

The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine. Thedefinitions “halogenated”, “partially or fully halogenated”; partiallyor fully fluorinated; “substituted by one or more halogen atoms”,includes for example, mono, di or tri halo derivatives on one or morecarbon atoms. For alkyl, a non-limiting example would be —CH₂CHF₂, —CF₃etc.

Each alkyl, cycloalkyl, heterocycle, aryl or heteroaryl, or the analogsthereof, described herein shall be understood to be optionally partiallyor fully halogenated.

As used herein, “nitrogen” or N and “sulfur” or S includes any oxidizedform of nitrogen and sulfur and the quaternized form of any basicnitrogen. For example, for an —S—C₁₋₆ alkyl radical, unless otherwisespecified, this shall be understood to include —S(O)—C₁₋₆ alkyl and—S(O)₂—C₁₋₆ alkyl, likewise, —S—R_(a) may be represented asphenyl-S(O)_(m)— when R_(a) is phenyl and where m is 0, 1 or 2.

GENERAL SYNTHETIC METHODS AND SYNTHESIS OF INTERMEDIATES

The compounds of the invention may be prepared by the methods andexamples presented below and methods known to those of ordinary skill inthe art. The methods that are described here are intended as anillustration and for the enablement of the instant invention withoutrestricting the scope of its subject matter, the claimed compounds, andthe examples. Optimum reaction conditions and reaction times may varydepending on the particular reactants used. Unless otherwise specified,solvents, temperatures, pressures, and other reaction conditions may bereadily selected by one of ordinary skill in the art. Specificprocedures are provided below. Intermediates used in the syntheses beloware either commercially available or easily prepared by methods known tothose skilled in the art. Reaction progress may be monitored byconventional methods such as thin layer chromatography (TLC) or highpressure liquid chromatography-mass spec (HPLC-MS). Intermediates andproducts may be purified by methods known in the art, including columnchromatography, HPLC, preparative TLC, supercritical fluidchromatography (SFC), and recrystallization.

Intermediate A1: Synthesis of 8-bromo-1H-pyrano[4,3-c]pyridin-4-one

A solution of 3,5-dibromo-pyridine-4-carbaldehyde (300 g, 1.1 mol) inmethanol (1.5 L) is cooled down to 0° C. and sodium borohydride (64 g,1.7 mol) is added. Then the reaction mixture is stirred for 2 hr beforeice is added. The solvent is removed and the mixture is extracted withDCM (3×500 mL). The organic layers are combined, dried over Na₂SO₄ andconcentrated to give 280 g of (3,5-dibromo-pyridin-4-yl)-methanol.

A solution of (3,5-dibromo-pyridin-4-yl)-methanol (280 g, 1.0 mol) inTHF (1.2 L) is cooled down to 0° C. and 60% NaH in mineral oil (100 g,2.5 mol) is added. The reaction mixture is stirred for 30 min and allylbromide (250 g, 2.1 mol) is added. The reaction mixture is warmed up toroom temperature for 12 hr before ice is added. The mixture is extractedwith EtOAc (2×800 mL) and the organic layers are combined andconcentrated to give the crude product. Purification by flash silicacolumn chromatography affords 250 g of4-allyloxymethyl-3,5-dibromo-pyridine.

To a stirred solution of the 4-allyloxymethyl-3,5-dibromo-pyridine (100g, 330 mmol) in acetonitrile (600 mL) in a sealed tube are addedpalladium acetate (22 g, 97 mmol), triethyl amine (33 g, 330 mmol) andtriphenylphosphine (26 g, 97 mmol). The tube is sealed and heated at100° C. for 2 hr. Water is added and the mixture is extracted withEtOAc. The organic layers are combined, dried over Na₂SO₄ andconcentrated to give the crude product. Purification by flash silicacolumn chromatography affords 55 g of8-bromo-4-methylene-3,4-dihydro-1H-pyrano[4,3-c]pyridine.

To a stirred solution of8-bromo-4-methylene-3,4-dihydro-1H-pyrano[4,3-c]pyridine (20 g, 88 mmol)in THF (200 mL) and water (200 mL) are added osmium tetraoxide (4.5 g,18 mmol) and sodium periodate (41 g, 190 mmol). The reaction mixture isheated at 70° C. for 2 hr. After it is cooled down to room temperature,the reaction mixture is filtered through diatomaceous earth and thefiltrate is extracted with EtOAc. The combined organic layers are driedover anhydrous Na₂SO₄ and concentrated to give the crude product.Purification by flash silica column chromatography affords 13 g of thetitle product.

Intermediate A2, A3 and A4: Syntheses of8-bromo-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol and its Enantiomers

Intermediate A1 (10 g, 44 mmol) is dissolved in MeOH (200 mL) and sodiumborohydride (5.0 g, 130 mmol) is added. The reaction mixture is stirredat room temperature for 1 hr and the solvent is removed. The residue isdiluted with EtOAc (200 mL), washed with water (2×100 mL) and brine(1×100 mL). The organic layer is separated, dried over anhydrous Na₂SO₄and concentrated to give 10 g of racemic8-bromo-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol (Intermediate A2).

Chiral separation of the racemic Intermediate A2 (10 g, 44 mmol) usingSupercritical Fluid Chromatography affords 4.0 g of Enantiomer I(Intermediate A3, 3.26 min) and 4.1 g of Enantiomer II (Intermediate A4,4.34 min). The retention times are measured using the followingconditions: Regis RegisPack analytical Column, Mobile phase 10% (1:1:1MeOH:EtOH:iPA):CO₂ @ 3 mL/min, 200 bar, 40° C.

Intermediate A5: Synthesis of8-bromo-4-methyl-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol

Intermediate A1 (2.0 g, 8.8 mmol) is dissolved in THF (80 mL) and 3.0 Mmethyl magnesium bromide ether solution (5.9 mL, 18 mmol) is added. Themixture is stirred for 1 hr before another 1 mL of methyl magnesiumbromide ether solution is added. The reaction is stirred for another 30min and saturated aqueous NH₄Cl solution (15 mL) is added along withwater (15 mL) and EtOAc (100 mL). The mixture is stirred for 10 min andthe aqueous layer is separated and extracted with EtOAc. The organiclayers are combined and concentrated to give the crude product.Purification by flash column chromatography affords 1.2 g of the titleproduct.

Intermediate A6: Synthesis of8-bromo-3,4-dihydro-1H-pyrano[4,3-c]pyridine-4-carbonitrile

Intermediate A1 (7.0 g, 31 mmol) is dissolved in DCM (100 mL), thenpotassium tert-butoxide (4.1 g, 37 mmol) and1-isocyanomethanesulfonyl-4-methyl-benzene (6.6 g, 34 mmol) are added at0° C. The reaction mixture is stirred for 2 hr and it is quenched withice water. The mixture is extracted with DCM and all the organic layersare combined and concentrated to give the crude product. Purification byflash column chromatography affords 300 mg of the title product.

Intermediate A7 and A8: Syntheses of8-bromospiro[1,4-dihydropyrano[4,3-c]pyridine-3,1′-cyclopropane]-4-oland its Enantiomers

To a stirred solution of methyl 2-chloroethyl sulfide (9.7 g, 88 mmol)in acetonitrile (300 mL) is added methyl iodide (12 g, 88 mmol) at 0° C.and the mixture is warmed to room temperature for 16 hr. Then themixture is concentrated and the residue is washed with mixture ofmethanol and diethyl ether (1:3). A solid is formed and it is collectedby filtration. The solid is mixed with. Intermediate A1 (10 g, 44 mmol)in tert-butanol (200 mL) and potassium tert-butoxide (9.8 g, 88 mmol) isadded. The reaction mixture is heated at 70° C. for 2 hr and then wateris added to quench the reaction. The mixture is extracted with EtOAc andthe organic layers are combined and concentrated to give the crudeproduct. Purification by flash silica column chromatography affords 3.5g of 8-bromospiro[1H-pyrano[4,3-c]pyridine-3,1′-cyclopropane]-4-one.

To a stirred solution of8-bromospiro[1H-pyrano[4,3-c]pyridine-3,1′-cyclopropane]-4-one (3.5 g,14 mmol) in methanol (70 mL) cooled at 0° C. is added sodium borohydride(0.51 g, 14 mmol) batch wise. The reaction mixture is warmed up to roomtemperature for 1 hr before the solvent is removed. Ice is added to theresidue and the mixture is extracted with EtOAc. The organic layers arecombined and concentrated to give the crude product. Purification byflash column chromatography affords 2.7 g of racemic8-bromospiro[1,4-dihydropyrano[4,3-c]pyridine-3,1′-cyclopropane]-4-ol.

Chiral separation of the racemic8-bromospiro[1,4-dihydropyrano[4,3-c]pyridine-3,1′-cyclopropane]-4-ol(2.7 g, 11 mmol) using Supercritical Fluid Chromatography affords 1.0 gof Enantiomer I (Intermediate A7, 2.43 min) and 1.1 g of Enantiomer II(Intermediate A8, 3.32 min). The retention times are measured using thefollowing conditions: LUX Cellulose-2, 4.6×100 mm Column, Mobile phase15% (1:1:1 MeOH:EtOH:iPA):CO₂ @ 3 mL/min, 200 bar, 40° C.

Intermediate A9 and A10: Syntheses of(8-bromo-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl)-carbamic AcidTert-Butyl Ester and its Enantiomers

Intermediate A1 (3.0 g, 13 mmol) and titanium isopropoxide (8.6 mL, 29mmol) are mixed in 2.0 M ammonia ethanol solution (99 mL, 196 mmol). Themixture is stirred at room temperature for 16 hr, then sodiumborohydride (1.0 g, 26 mmol) is added. The reaction is continued foranother 3 hr and the solvent is removed to give the crude8-bromo-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ylamine which is used inthe next step without purification.

The crude 8-bromo-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ylamine (3.0 g,13 mmol) is dissolved in THF (90 mL) and di-tert-butyl dicarbonate (14g, 62 mmol) is added. The mixture is stirred for 40 hr and saturatedaqueous NH₄Cl solution (10 mL) is added. After stiffing the mixture for10 min, saturated aqueous NaHCO₃ solution (20 mL) is added. The mixtureis again stirred for 10 min and a solid is formed. The solid is filteredand the filtrate is extracted with EtOAc (3×150 mL). The organic layersare combined and concentrated to give the crude product. Purification byflash column chromatography affords 2.8 g of the title product(racemate).

Chiral separation of the racemic(8-bromo-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl)-carbamic acidtert-butyl ester (2.8 g, 8.4 mmol) using Supercritical FluidChromatography affords 1.2 g of Enantiomer I (Intermediate A9, 1.61 min)and 1.2 g of Enantiomer II (Intermediate A10, 2.50 min). The retentiontimes are measured using the following conditions: RegisPack analyticalColumn, Mobile phase 10% (1:1:1 MeOH:EtOH:iPA):CO₂ @ 3 mL/min, 200 bar,40° C.

Intermediate A11: Synthesis of Enantiomerically PureN-(8-bromo-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl)-propionamide

Enantiomerically pure Intermediate A3 (4.0 g, 17 mmol) anddiphenylphosphoryl azide (4.9 mL, 23 mmol) are dissolved in THF (100 mL)and the reaction mixture is cooled down to 0° C.1,8-Diazabicyclo[5.4.0]undec-7-ene (3.4 mL, 23 mmol) is added dropwiseand the mixture is warmed to room temperature for 1 hr and heated at 45°C. for 3 hr. Then the reaction mixture is cooled down to roomtemperature and stirred for another 16 hr. The resulting mixture is usedin the next step without workup or purification.

Triphenylphosphine (6.0 g, 23 mmol) is added into the reaction mixtureobtained from the previous step and the mixture is heated at 60° C. for2 hr. After it is cooled down to room temperature, water (24 mL) isadded and the mixture is heated at 65° C. for 3 hr. After the mixture iscooled down to room temperature, it is used in the next step withoutworkup or purification.

Di-tert-butyl dicarbonate (20 g, 92 mmol) is added into the reactionmixture obtained from the previous step and the resulting mixture isstirred for 16 hr. Then water (300 mL) is added along with 100 mL ofEtOAc. The mixture is stirred for 5 min and the aqueous layer isseparated and extracted with EtOAc (3×100 mL). All the organic layersare combined and concentrated to give the crude product. Purification byflash column chromatography affords 4.0 g of enantiomerically pure(8-bromo-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl)-carbamic acidtert-butyl ester.

Enantiomerically pure(8-bromo-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl)-carbamic acidtert-butyl ester (4.0 g, 12 mmol) is dissolved in DCM (120 mL) andtrifluoroacetic acid (10 mL) is added. The mixture is stirred for 3 hrand saturated aqueous NaHCO₃ solution (20 mL) is added along with 10 mLof water. The mixture is stirred for 10 min and the aqueous layer isseparated and extracted with DCM (3×75 mL) and EtOAc (6×75 mL). All theorganic layers are combined and concentrated to give 2.8 g of the crude8-bromo-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ylamine which is usedwithout purification.

8-Bromo-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ylamine (1.4 g, 6.1 mmol),propionic acid (0.54 mL, 7.3 mmol) and triethyl amine (2.5 mL, 18 mmol)are mixed in acetonitrile (60 mL), then0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(2.3 g, 7.3 mmol) is added. The mixture is stirred for 60 hr and all thesolvents are removed. The residue is purified by flash columnchromatography to give 1.5 g of the title product.

Intermediate A12: Synthesis of Enantiomerically Pure Ethanesulfonic Acid(8-bromo-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl)-amide

Procedures of Step 1 to Step 4 are described above for Intermediate A11.The crude 8-bromo-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ylamine isobtained by following these procedures.

8-Bromo-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ylamine (1.4 g, 6.1 mmol)is dissolved in DCM (60 mL) and triethyl amine (0.93 mL, 6.7 mmol) isadded. Then ethanesulfonyl chloride (0.63 mL, 6.7 mmol) is added slowlyand the mixture is stirred for 35 min. The saturated aqueous NaHCO₃solution (15 mL) is added along with water (15 mL). The mixture isstirred for 10 min and the organic layer is separated. The aqueous layeris extracted with DCM (2×45 mL) and all organic layers are combined andconcentrated to give the crude product. Purification by flash columnchromatography affords 1.6 g of the title product.

Intermediate A13: Synthesis of 5-bromo-1H-pyrano[3,4-c]pyridin-4-one

A stirred solution of 5-bromo nicotinic acid (30 g, 150 mmol) in dry THF(500 mL) is cooled down to −70° C. Freshly made lithium diisopropylamide(240 mmol, from 53 mL of diisopropylamine and 150 mL of 1.6 M n-BuLi inTHF) is added dropwise and the mixture is stirred for 2.5 hr at −55° C.before it is cooled down to −70° C.1,2-Dibromo-1,1,2,2-tetrachloro-ethane (50 g, 150 mmol) is added over 30min and the mixture is stirred for 30 min before it is warmed to −20° C.over 2 hr. Then water (150 mL) is added and the pH of the reactionmixture is adjusted to 3 by adding concentrated HCl. A solid is formedand it is filtered, rinsed with pentane to give 25 g of4,5-dibromo-nicotinic acid.

To a stirred solution of 4,5-dibromo-nicotinic acid (50 g, 180 mmol) inDMF (300 mL) is added potassium carbonate (49 g, 360 mmol) at 0° C. Themixture is stirred for 15 min and methyl iodide (38 g, 270 mmol) isadded at 0° C. Then the reaction mixture is slowly warmed up to roomtemperature for 12 hr. Icy water is added and a solid is formed. Thesolid is filtered and dissolved in DCM. The solvent is removed to givethe crude product. Purification by flash column chromatography affords30 g of 4,5-dibromo-nicotinic acid methyl ester.

To a stirred solution of 4,5-dibromo-nicotinic acid methyl ester (30 g,100 mmol) in methanol (300 mL) cooled at 0° C. is added sodiumborohydride (11 g, 290 mmol). The reaction mixture is warmed to roomtemperature for 1 hr. The solvent is removed and ice is added. Themixture is extracted with EtOAc and the organic layers are combined,dried and concentrated to give 21 g of(4,5-dibromo-pyridin-3-yl)-methanol.

To a stirred solution of (4,5-dibromo-pyridin-3-yl)-methanol (21 g, 79mmol) in THF (200 mL) cooled at 0° C. is added 60% sodium hydride (3.8g, 160 mmol). The mixture is stirred for 30 min at 0° C. and allylbromide (19 g, 160 mmol) is added. Then the reaction is warmed to roomtemperature for 12 hr. Ice is added and the mixture is extracted withEtOAc. The organic layers are separated, dried and concentrated to givethe crude product. Purification by flash column chromatography affords10 g of 3-allyloxymethyl-4,5-dibromo-pyridine.

To a stirred solution of 3-allyloxymethyl-4,5-dibromo-pyridine (8.0 g,26 mmol) in acetonitrile 120 mL) are added triethyl amine (7.9 g, 78mmol), triphenylphosphine (4.1 g, 16 mmol) and palladium acetate (2.3 g,10 mmol). The mixture is heated at 100° C. for 2 hr before it is cooleddown to room temperature. Water is added and the mixture is extractedwith EtOAc. The organic layers are combined, dried and concentrated togive the crude product. Purification by flash column chromatographyaffords 1.2 g of5-bromo-4-methylene-3,4-dihydro-1H-pyrano[3,4-c]pyridine.

To a stirred solution of5-bromo-4-methylene-3,4-dihydro-1H-pyrano[3,4-c]pyridine (1.2 g, 5.3mmol) in THF (20 mL) and water (20 mL) are added sodium periodate (2.5g, 12 mmol) and osmium tetraoxide (270 mg, 1.1 mmol). The mixture isstirred at room temperature for 2 hr and then the solvent is removed.The residue is extracted with EtOAc and the organic layers are combined,dried and concentrated to give the crude product. Purification by flashcolumn chromatography affords 260 mg of the title product.

Intermediate B1: Synthesis of 3-bromo-quinoline-8-carboxylic Acid Amide

3-Bromo-quinoline-8-carboxylic acid (900 mg, 3.6 mmol) is dissolved inDMF (27 mL) and CDI (1.3 g, 7.9 mmol) is added. The mixture is heated at60° C. for 16 hr before it is cooled down to room temperature. Then 28%ammonium hydroxide aqueous solution (4.5 g, 36 mmol) is added and themixture is stirred for another 1 hr. The saturated NaHCO₃ aqueoussolution (30 mL) is added along with water (30 mL). A white solid isformed and it is filtered, rinsed with more water and dried to give 650mg of the title product.

Intermediate B2: Synthesis of1-(5-bromo-1,3-dihydro-isoindol-2-yl)-ethanone

5-Bromo-2,3-dihydro-1H-isoindole (1.0 g, 5.0 mmol) is dissolved in DCM(50 mL) and acetyl chloride (7.6 mL, 7.6 mmol) and triethyl amine (1.4mL, 10 mmol) are added. The mixture is stirred for 1 hr before saturatedNaHCO₃ aqueous solution (30 mL) and water (30 mL) are added. The mixtureis stirred for 10 min and the organic layer is separated. The aqueouslayer is extracted with DCM (2×35 mL) and all the organic layers arecombined and concentrated to give the crude product. Purification byflash column chromatography affords 850 mg of the title product.

Intermediate B3: Synthesis of6-bromo-1-methyl-1H-indazole-3-carbonitrile

6-Bromo-1H-indazole-3-carbonitrile (500 mg, 2.3 mmol) is dissolved inTHF (20 mL) and 60% sodium hydride (140 mg, 3.4 mmol) is added. Afterstiffing for 10 min, methyl iodide (0.28 mL, 4.5 mmol) is added and themixture is stirred for 16 hr. Then saturated NH₄Cl aqueous solution (5mL) is added along with EtOAc (30 mL) and water (15 mL). The mixture isstirred for 5 min and the aqueous layer is separated and extracted withEtOAc (2×20 mL). All organic layers are combined and concentrated togive the crude product. Purification by flash column chromatographyaffords 320 mg of the title product.

Intermediate B4: Synthesis of6-bromo-1-methyl-1H-indazole-4-carbonitrile

6-Bromo-1H-indazole-4-carbonitrile (500 mg, 2.3 mmol) is dissolved inTHF (20 mL) and 60% sodium hydride (140 mg, 3.4 mmol) is added. Afterstiffing for 10 min, methyl iodide (0.28 mL, 4.5 mmol) is added and themixture is stirred for 16 hr. Then saturated NH₄Cl aqueous solution (5mL) is added along with EtOAc (30 mL) and water (15 mL). The mixture isstirred for 5 min and the aqueous layer is separated and extracted withEtOAc (2×20 mL). All organic layers are combined and concentrated togive the crude product. Purification by flash column chromatographyaffords 290 mg of the title product.

Intermediate B5: Synthesis of 6-bromo-4-fluoro-1-methyl-1H-indazole

6-Bromo-4-fluoro-1H-indazole (2.4 g, 11 mmol) is dissolved in THF (100mL) and 60% sodium hydride (680 mg, 17 mmol) is added. After stiffingfor 10 min, methyl iodide (1.4 mL, 23 mmol) is added and the mixture isstirred for 16 hr. Then saturated NH₄Cl aqueous solution (25 mL) isadded along with EtOAc (50 mL) and water (35 mL). The mixture is stirredfor 5 min and the aqueous layer is separated and extracted with EtOAc(2×50 mL). All organic layers are combined and concentrated to give thecrude product. Purification by flash column chromatography affords 1.0 gof the title product.

Intermediate B6: Synthesis of7-bromo-2,3-dihydro-5H-benzo[e][1,4]dioxepine

To a stirred solution of 4-bromo-2-hydroxymethyl-phenol (10 g, 49 mmol)in ethylene glycol (57 g, 910 mmol) is added p-toluenesulfonic acid (1.0g, 6.0 mmol) at room temperature. The mixture is heated up to 100° C.for 4 hr. Then ice is used to quench the reaction and the mixture isextracted with EtOAc. The organic layer is separated, dried andconcentrated to give the crude product. Purification by flash columnchromatography affords 8.0 g of4-bromo-2-(2-hydroxy-ethoxymethyl)-phenol.

To a stirred solution of 4-bromo-2-(2-hydroxy-ethoxymethyl)-phenol (7.0g, 28 mmol) in DCM (300 mL) at 0° C. is added triphenylphosphine (11 g,42 mmol) and diisopropyl azodicarboxylate (6.9 g, 34 mmol). The reactionmixture is slowly warmed to room temperature for 16 hr. Then thereaction is quenched with ice water and extracted with DCM. The organiclayer is separated and concentrated to give the crude product.Purification by flash silica column chromatography affords 1.8 g of thetitle product.

Intermediate B7 and B8: Syntheses of the Enantiomers of6-bromo-chroman-4-ol

To a stirred solution of 6-bromo-chroman-4-one (4.0 g, 18 mmol) inmethanol (100 mL) at 0° C. is added sodium borohydride (1.0 g, 26 mmol)slowly. The reaction mixture is warmed to room temperature for 2 hr.Then it is cooled down to 0° C. and NaHCO₃ solution is added to quenchthe reaction. The mixture is warmed to room temperature and extractedwith DCM. The organic layer is separated, dried and concentrated to give3.5 g of racemic 6-bromo-chroman-4-ol.

Chiral separation of the racemic 6-bromo-chroman-4-ol (3.5 g, 15 mmol)using Supercritical Fluid Chromatography affords 1.5 g of Enantiomer I(Intermediate B7, 2.10 min) and 1.5 g of Enantiomer II (Intermediate B8,2.69 min). The retention times are measured using the followingconditions: LUX 5 u Cellulose 3 Analytical Column, Mobile phase 5%(1:1:1 MeOH:EtOH:iPA): CO₂ @ 3 mL/min, 200 bar, 40° C.

Intermediate B9 and B10: Syntheses of the Enantiomers of6-bromo-4-methyl-chroman-4-ol

To a stirred solution of 6-bromo-chroman-4-one (6.7 g, 30 mmol) in THF(70 mL) is added cerium(III) chloride (3.6 g, 15 mmol) and the mixtureis cooled down to −50° C. Then 3.0 M MeMgI in diethyl ether (30 mL, 90mmol) is added dropwise and the reaction mixture is warmed to 15° C. in45 min. The saturated aqueous NH₄Cl solution is added and the mixture isextracted with EtOAc (2×50 mL). The organic layers are combined andconcentrated to give the crude product. Purification by flash columnchromatography affords 3.5 g of racemic 6-bromo-4-methyl-chroman-4-ol.

Chiral separation of the racemic 6-bromo-4-methyl-chroman-4-ol (3.5 g,14 mmol) using Supercritical Fluid Chromatography affords 1.0 g ofEnantiomer I (Intermediate B9, 1.22 min) and 1.3 g of Enantiomer II(Intermediate B10, 2.15 min). The retention times are measured using thefollowing conditions: LUX Amylose-2 4.6×250 mm Column, Mobile phase 10%(1:1:1 MeOH:EtOH:iPA):CO₂ @ 3 mL/min, 200 bar, 40° C.

Intermediate B11: Synthesis of 6-bromo-4,4-difluoro-chroman

To a stirred solution of 6-bromo-chroman-4-one (5.0 g, 22 mmol) in DCM(100 mL) at 0° C. are added 1,2-ethanedithiol (4.1 g, 44 mmol) and borontrifluoride etherate (1.6 g, 11 mmol). The reaction mixture is stirredat room temperature for 16 hr before it is poured into 1.0 N NaOHsolution. The mixture is extracted with DCM and the organic layers areseparated, dried and concentrated to give the crude product. Washing thecrude product with n-pentane affords 4.1 g of6′-bromospiro[1,3-dithiolane-2,4′-chromane].

A suspension of N-iodosuccinimide (6.1 g, 27 mmol) in DCM (80 mL) iscooled down to −70° C. Hydrogen fluoride pyridine complex (5.4 g, 54mmol) is added dropwise. A solution of6′-bromospiro[1,3-dithiolane-2,4′-chromane] (4.1 g, 14 mmol) in DCM(cooled at −70° C.). is added dropwise and the mixture is stirred at−70° C. for 30 min. Then the reaction solution is poured into a mixtureof hexane and DCM and the resulting mixture is filtered through a shortpad of silica gel. The filtrate is concentrated to give the crudeproduct. Purification by flash silica column chromatography affords 1.1g of the title product.

Intermediate B12: Synthesis of8-bromo-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one

To a stirred solution of 7-bromo-chroman-4-one (1.0 g, 4.4 mmol) in DCM(40 mL) at 0° C. are added sodium azide (430 mg, 6.6 mmol) andmethanesulfonic acid (6.3 g, 66 mmol). The reaction mixture is stirredat 0° C. for 4 hr before water is added. The mixture is extracted withDCM and the organic layer is separated and concentrated to give thecrude product. Purification by flash silica column chromatographyaffords 560 mg of the title product.

Intermediate B13: Synthesis of8-bromo-5,5-difluoro-1,3,4,5-tetrahydro-benzo[c]oxepine

To a stirred solution of 2,5-dibromo-benzoic acid ethyl ester (90 g, 290mmol) in ethanol (900 mL) at 0° C. is added sodium borohydride (33 g,880 mmol). The mixture is stirred at room temperature for 12 hr and thenrefluxed for 20 hr. The solvent is removed and water is added to theresidue. The mixture is extracted with EtOAc and the organic layers arecombined and concentrated to give the crude product. Purification byflash column chromatography affords 35 g of(2,5-dibromo-phenyl)-methanol.

To a stirred solution of (2,5-dibromo-phenyl)-methanol (40 g, 150 mmol)and triphenylphospine (59 g, 230 mmol) in THF (1000 mL) at 0° C. isadded carbon tetrabromide (75 g, 230 mmol) slowly. The reaction mixtureis stirred at room temperature for 2 hr and the solvent is removed togive the crude product. Purification by flash column chromatographyaffords 40 g of 1,4-dibromo-2-bromomethyl-benzene.

To a stirred solution of 3-buten-1-ol (13 g, 180 mmol) in THF (500 mL)at 0° C. is added 60% sodium hydride (7.3 g, 180 mmol). The mixture isstirred for 30 min at 0° C. before 1,4-dibromo-2-bromomethyl-benzene (40g, 120 mmol) in THF (300 mL) is added. Then the reaction mixture isallowed to warm up to room temperature for 12 hr and ice is added toquench the reaction. The mixture is extracted with EtOAc and the organiclayers are combined, dried and concentrated to give the crude product.Purification by flash column chromatography affords 25 g of1,4-dibromo-2-but-3-enyloxymethyl-benzene.

To a stirred solution of 1,4-dibromo-2-but-3-enyloxymethyl-benzene (25g, 78 mmol) in acetonitrile (1000 mL) silver carbonate (26 g, 94 mmol)is added. Then tetrakis(triphenylphosphine)palladium(0) (9.0 g, 7.8mmol) is added after the reaction mixture is purged with argon gas for10 min. The reaction mixture is heated at 100° C. for 24 hr. The solventis removed and the residue is extracted with EtOAc. The organic solutionis then concentrated to give the crude product. Purification by flashcolumn chromatography affords 10 g of8-bromo-5-methylene-1,3,4,5-tetrahydro-benzo[c]oxepine.

To a stirred solution of8-bromo-5-methylene-1,3,4,5-tetrahydro-benzo[c]oxepine (10 g, 42 mmol)in THF/Water (400 mL, 1:1) at 0° C. are added sodium periodate (20 g, 93mmol) and osmium tetraoxide (2.1 g, 8.2 mmol). The reaction mixture isthen warmed up to room temperature for 1 hr before it is diluted withwater. The mixture is extracted with EtOAc and the organic layer isseparated, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated to give the crude product. Purification by flash columnchromatography affords 4.0 g of8-bromo-3,4-dihydro-1H-benzo[c]oxepin-5-one.

To a stirred solution of 8-bromo-3,4-dihydro-1H-benzo[c]oxepin-5-one(3.5 g, 15 mmol) in DCM (10 mL) is added diethylaminosulfur trifluoride(9.4 g, 58 mmol). The mixture is refluxed for 14 hr before methanol isadded. Then saturated aqueous NaHCO₃ solution is added and the organiclayer is separated. The aqueous layer is extracted with DCM and all theorganic layers are combined, washed with brine, dried over anhydrousNa₂SO₄ and concentrated to give the crude product. Purification by flashcolumn chromatography affords 1.7 g of the title product.

Intermediate B14: Synthesis of3-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole

To a stirred solution of 6-bromo-1-methyl-1H-indazole (20 g, 95 mmol) inacetonitrile (300 mL) is added1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (42 g, 120 mmol) and the reaction mixture isheated at 90° C. for 2 hr. Water is added and the mixture is extractedwith EtOAc. The organic layers are combined, dried over Na₂SO₄ andconcentrated to give the crude product. Purification by flash columnchromatography affords 6.0 g of 6-bromo-3-fluoro-1-methyl-1H-indazole.

To a stirred solution of 6-bromo-3-fluoro-1-methyl-1H-indazole (5.0 g,22 mmol) in 1,4-dioxane (100 mL) are added bis(pinacolato)diboron (3.5g, 14 mmol) and potassium acetate (3.5 g, 36 mmol). The mixture ispurged with argon gas for 10 min anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (1.0 g, 1.0mmol) is added. The reaction mixture is heated at 100° C. for 5 hr andwater is added. The mixture is extracted with EtOAc and the organiclayers are combined and concentrated to give the crude product.Purification by flash column chromatography affords 2.0 g of the titleproduct.

Intermediate B15: Synthesis of6-bromo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic Acid Amide

To a cooled (0° C.) solution6-bromo-3,4-dihydro-1H-[1,8]naphthyridin-2-one (10 g, 44 mmol) in THF(500 mL) is added sodium borohydride (8.3 g, 220 mmol) followed by borontrifluoride diethyl ether complex (39 mL, 310 mmol) dropwise. Theresulting mixture is allowed to warm to room temperature and it isstirred for 16 hr. The reaction is carefully quenched with the dropwiseaddition of 1.0 N HCl aqueous solution (15 mL). Once quenched,additional 1.0 N HCl aqueous solution (85 mL) is added and the mixtureis stirred at room temperature for 16 hr. The mixture is thenconcentrated, diluted with water and made basic (pH 8) with the additionof powdered sodium bicarbonate. The mixture is extracted with EtOAc andthe combined organic layers are washed with brine, dried over Na₂SO₄ andconcentrated to give 9.3 g of6-bromo-1,2,3,4-tetrahydro-[1,8]naphthyridine.

To a cooled (0° C.) solution of6-bromo-1,2,3,4-tetrahydro-[1,8]naphthyridine (6.4 g, 30 mmol) in DCM(75 mL) is added trichloroacetyl isocyanate (3.8 mL, 32 mmol). Afterstiffing for 1 hr at 0° C., a solution of methanolic KOH (1.0 M, 10 mL)is added. The resulting mixture is allowed to warm up to roomtemperature and it is stirred for 16 hr. The reaction mixture isconcentrated to give the crude product. Purification by flash columnchromatography affords 7.4 g of the title product.

Intermediate B16: Synthesis of Trifluoro-Methanesulfonic Acid4-cyano-cyclohex-1-enyl ester

4-Oxo-cyclohexanecarbonitrile (2.0 g, 16 mmol) is dissolved in THF (100mL) and it is cooled down to −78° C. Then 2.0 M lithium diisopropylamideTHF solution (9.5 mL, 19 mmol) is added and the mixture is stirred for30 min at −78° C. 2[N,N-bis(trifluoromethylsulfonyl)amino]pyridine (7.0g, 20 mmol) is added and the mixture is allowed to warm to roomtemperature and it is stirred for 16 hr. Then 200 mL of EtOAc is addedalong with 100 mL of saturated aqueous NH₄Cl solution. The organic layeris separated and washed with 100 mL of water and 100 mL of brine beforeit is concentrated to give the crude product. Purification by flashcolumn chromatography affords 1.9 g of the title product.

Intermediate B17: Synthesis of Trifluoro-Methanesulfonic Acid1-methyl-4,5-dihydro-1H-indazol-6-yl ester

To a suspension of 60% NaH (12 g, 290 mmol) in 200 mL of Et₂O is addedEtOH (17 mL, 300 mmol) at 4° C. The mixture is stirred for 30 min before3-ethoxy-cyclohex-2-enone (7.0 g, 50 mmol) is added. The mixture isstirred for 1 hr and it is cooled down to 0° C. Then formic acid ethylester (12 mL, 150 mmol) is added and the mixture is stirred for 18 hr.Water (200 mL) is added along with EtOAc (400 mL). The organic layer isremoved and the aqueous layer is acidified to pH 4 and buffered with 2 MKHCO₃. Then the aqueous layer is extracted with DCM (2×300 mL) and theDCM layers are dried and concentrated to give 8.3 g of3-ethoxy-6-[1-hydroxy-meth-(Z)-ylidene]-cyclohex-2-enone.

To the solution of3-ethoxy-6-[1-hydroxy-meth-(Z)-ylidene]-cyclohex-2-enone (8.3 g, 49mmol) in EtOH (40 mL) is added methylhydrazine (13 mL, 250 mmol). Themixture is stirred for 16 hr before it is concentrated to give the crudeproduct. Purification by flash column chromatography affords 3.6 g of6-ethoxy-1-methyl-4,5-dihydro-1H-indazole.

6-Ethoxy-1-methyl-4,5-dihydro-1H-indazole (3.6 g, 20 mmol) is added intothe 1.0 N HCl solution (15 mL). The mixture is stirred for 3 hr beforeit is made basic by the addition of solid NaHCO₃. The mixture is thenextracted with DCM (3×120 mL) and all the organic layers are combined,dried over anhydrous MgSO₄ and concentrated to give 2.8 g of1-methyl-1,4,5,7-tetrahydro-indazol-6-one.

1-Methyl-1,4,5,7-tetrahydro-indazol-6-one (2.5 g, 17 mmol) is dissolvedin DCM (200 mL) and the solution is cooled down to 4° C. Then2,6-di-tert-butyl-4-methyl-pyridine (5.2 g, 25 mmol) is added followedby the addition of trifluoromethanesulfonic anhydride (4.2 mL, 25 mmol).The mixture is allowed to warm to room temperature and stir for 16 hr.EtOAc (400 mL) is added along with water (200 mL). The organic layer isseparated, washed with 200 mL of water, 200 mL of saturated NH₄Cl and200 mL of brine before it is concentrated to give the crude product.Purification by flash column chromatography affords 2.3 g of the titleproduct.

Intermediate B18: Synthesis of4,4-difluoro-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isochroman

To a stirred solution of (2,5-dibromo-phenyl)-methanol (45 g, 170 mmol)in THF (1000 mL) is added 60% NaH in mineral oil (10 g, 250 mmol) at 0°C. The mixture is stirred for 30 min and allyl bromide (25 g, 203 mmol)is added. Then the mixture is warmed up to room temperature for 12 hrs.The reaction is quenched with ice and the mixture is extracted withEtOAc. The organic layers are combined, dried and concentrated to givethe crude product. Purification by flash column chromatography affords45 g of 2-allyloxymethyl-1,4-dibromo-benzene.

To a stirred solution of 2-allyloxymethyl-1,4-dibromo-benzene (14 g, 46mmol) in DMF (500 mL) are added Cs₂CO₃ (30 g, 92 mmol) andtetrabutylammonium iodide (17 g, 46 mmol). The reaction mixture ispurged with argon gas for 10 min andtetrakis(triphenylphosphine)palladium(0) (5.3 g, 4.6 mmol) is added. Thereaction mixture is then heated at 100° C. for 12 hrs and water is thenadded. The mixture is extracted with EtOAc and organic layers are driedand concentrated to give the crude product. Purification by flash columnchromatography affords 5 g of 7-bromo-4-methylene-isochroman.

To a stirred solution of 7-bromo-4-methylene-isochroman (5.0 g, 22 mmol)in THF/water (200 mL, 1:1) are added sodium periodate (10 g, 49 mmol)and osmium tetraoxide (1.1 g, 4.0 mmol) at 0° C. The reaction mixture iswarmed up to room temperature for 1 hr. Then water is added and themixture is extracted with EtOAc. The organic layers are combined, washedwith brine, dried and concentrated to give the crude product.Purification by flash column chromatography affords 400 mg of7-bromo-isochroman-4-one.

To a stirred solution of 7-bromo-isochroman-4-one (400 mg, 1.8 mmol) inDCM (2.0 mL) is added diethylaminosulfur trifluoride (1.1 g, 6.8 mmol)at room temperature. The mixture is heated at 70° C. for 14 hrs. ThenMeOH is added along with saturated aqueous NaHCO₃.solution. The aqueouslayer is separated and extracted with DCM (2×20 mL). All the organiclayers are combined, washed with brine, dried and concentrated to givethe crude product. Purification by flash column chromatography affords200 mg of 7-bromo-4,4-difluoro-isochroman.

To a stirred solution of 7-bromo-4,4-difluoro-isochroman (500 mg, 2.0mmol) in 1,4-dioxane (20 mL) are added potassium acetate (590 mg, 6.0mmol) and bis(pinacolato)diboron (560 mg, 2.0 mmol). The reactionmixture is purged with argon for 15 min anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) DCM adduct(160 mg, 0.20 mmol) is added. The reaction mixture is then heated at100° C. for 14 hrs and water is added. The mixture is stirred for 10 minand it is extracted with EtOAc. The organic layers are combined, washedwith brine, dried and concentrated to give the crude product.Purification by flash column chromatography affords 300 mg of the titledproduct.

Example 1: Synthesis of8-(3-fluoro-1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol,Enantiomer II (Cpd 15, Table 1)

Intermediate B14 (72 mg, 0.26 mmol), Intermediate A4 (50 mg, 0.22 mmol)and 2.0 M aqueous Na₂CO₃ solution (0.22 mL, 0.44 mmol) are mixed in1,4-dioxane (2.0 mL). The reaction mixture is purged with argon gas for5 min. Then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (16 mg, 0.022 mmol) is added and the mixture is heated at100° C. for 3.5 hr. The solvents are removed and the residue is purifiedby flash column chromatography to give 38 mg of the title product.

Compounds 1 to 14, 16 to 69, 188 and 193 to 200 in Table 1 aresynthesized according to the procedure for Example 1, substitutingIntermediate B14 and/or Intermediate A4 with either commerciallyavailable reagents or the appropriate intermediates listed below.

Boronic Cpd No acid/ester Bromide 1 Commercial Intermediate A4 2Commercial Intermediate A3 3 Commercial Intermediate A3 4 CommercialIntermediate A3 5 Commercial Intermediate A4 6 Commercial IntermediateA4 7 Commercial Intermediate A3 8 Commercial Intermediate A3 9Commercial Intermediate A6 10 Commercial Intermediate A3 11 CommercialIntermediate A3 12 Commercial Intermediate A4 13 Commercial IntermediateA4 14 Commercial Intermediate A4 16 Commercial Intermediate A7 17Commercial Intermediate A8 18 Commercial Intermediate A4 19 CommercialIntermediate A3 20 Commercial Intermediate A3 21 Commercial IntermediateA3 22 Commercial Intermediate A3 23 Commercial Intermediate A3 24Commercial Intermediate A3 25 Commercial Intermediate A3 26 CommercialIntermediate A3 27 Commercial Intermediate A3 28 Commercial IntermediateA3 29 Commercial Intermediate A3 30 Commercial Intermediate A3 31Commercial Intermediate A3 32 Commercial Intermediate A4 33 CommercialIntermediate A4 34 Commercial Intermediate A4 35 Commercial IntermediateA4 36 Commercial Intermediate A4 37 Commercial Intermediate A4 38Commercial Intermediate A4 39 Commercial Intermediate A4 40 CommercialIntermediate A4 41 Commercial Intermediate A4 42 Commercial IntermediateA4 43 Commercial Intermediate A4 44 Commercial Intermediate A4 45Commercial Intermediate A4 46 Commercial Intermediate A4 47 CommercialIntermediate A4 48 Commercial Intermediate A4 49 Commercial IntermediateA4 50 Commercial Intermediate A4 51 Commercial Intermediate A4 52Commercial Intermediate A4 53 Commercial Intermediate A3 54 CommercialIntermediate A3 55 Intermediate B14 Intermediate A3 56 CommercialIntermediate A11 57 Commercial Intermediate A11 58 CommercialIntermediate A11 59 Commercial Intermediate A11 60 CommercialIntermediate A11 61 Commercial Intermediate A11 62 CommercialIntermediate A11 63 Commercial Intermediate A12 64 CommercialIntermediate A12 65 Commercial Intermediate A12 66 CommercialIntermediate A12 67 Commercial Intermediate A12 68 Intermediate B14Intermediate A12 69 Commercial Intermediate A12 188 CommercialIntermediate A3 193 Commercial Intermediate A11 194 Intermediate B18Intermediate A11 195 Commercial Intermediate A12 196 Intermediate B18Intermediate A12 197 Commercial Intermediate A7 198 CommercialIntermediate A8 199 Intermediate B18 intermediate A4 200 IntermediateB18 intermediate A3

Example 2: Synthesis8-(1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ylamine,Enantiomer II (Cpd 71, Table 1)

Intermediate A10 is coupled with (1-methylindazol-6-yl)boronic acidaccording to the procedure for Example 1 to give[8-(1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-carbamicacid tert-butyl ester in Step 1.

[8-(1-Methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-carbamicacid tert-butyl ester (410 mg, 1.1 mmol) is dissolved in DCM (2.0 mL)and trifluoroacetic acid (0.5 mL) is added. The mixture is stirred for16 hr at room temperature and saturated aqueous NaHCO₃ solution (5 mL)is added along with 10 mL of water. The mixture is stirred for 10 minand the aqueous layer is separated and extracted with DCM (3×15 mL) andEtOAc (3×15 mL). All the organic layers are combined and concentrated togive the crude product. Purification by flash column chromatographyaffords 303 mg of the title product.

Compound 70 in Table 1 is synthesized according to the procedures forExample 2, substituting (1-methylindazol-6-yl)boronic acid withcommercially available (1,5-dimethylindazol-6-yl)boronic acid in Step 1.

Example 3: Synthesis ofN-[8-(1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-isobutyramide,Enantiomer II (Cpd 77, Table 1)

Intermediate A10 and (1-methylindazol-6-yl)boronic acid are converted to8-(1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ylamineaccording to the procedures for Example 2 in Step 1 and Step 2.

8-(1-Methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ylamine(88 mg, 0.31 mmol), isobutyric acid (0.044 mL, 0.47 mmol) and triethylamine (0.13 mL, 0.94 mmol) are mixed in acetonitrile (2.0 mL). Then0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(120 mg, 0.38 mmol) is added and the mixture is stirred for 16 hr. Allthe solvent is removed and the residue is purified by flash columnchromatography to give 40 mg of the title product.

Compounds 72 to 76 in Table 1 are synthesized according to the procedurefor Example 3, substituting with either commercially available reagentsor the appropriate intermediates listed below.

Boronic Cpd No acid/ester Bromide 72 Commercial Intermediate A9 73Commercial Intermediate A10 74 Commercial Intermediate A10 75 CommercialIntermediate A10 76 Commercial Intermediate A10

Example 4: Synthesis of Ethanesulfonic Acid[8-(1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide,Enantiomer II (Cpd 83, Table 1)

Intermediate A10 and (1-methylindazol-6-yl)boronic acid are converted to8-(1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ylamineaccording to the procedures for Example 2 in Step 1 and Step 2.

8-(1-Methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ylamine(66 mg, 0.24 mmol) is dissolved in DCM (2.0 mL) and ethanesulfonylchloride (0.025 mL, 0.26 mmol) is added. Then triethyl amine (0.066 mL,0.47 mmol) is added and the mixture is stirred for 2 hr. All the solventis removed to give the crude product. Purification by flash columnchromatography affords 26 mg of the title product.

Compounds 78 to 82 in Table 1 are synthesized according to the procedurefor Example 4, substituting with either commercially available reagentsor the appropriate intermediates listed below.

Boronic Cpd No acid/ester Bromide 78 Commercial Intermediate A9 79Commercial Intermediate A10 80 Commercial Intermediate A9 81 CommercialIntermediate A10 82 Commercial Intermediate A10

Example 5: Synthesis of8-(4-fluoro-1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol,Enantiomer II (Cpd 96, Table 1)

Intermediate B5 (69 mg, 0.30 mmol), bis(pinacolato)diboron (95 mg, 0.38mmol) and potassium acetate (130 mg, 1.4 mmol) are mixed in 1,4-dioxane(3.0 mL) and the reaction mixture is purged with argon gas for 10 min.Then dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (22 mg,0.030 mmol) is added and the mixture is heated at 90° C. for 16 hr. Thereaction crude is cooled down to room temperature and it is used in thenext step without workup and purification.

Intermediate A4 (50 mg, 0.22 mmol) and 2.0 M aqueous Na₂CO₃ solution(0.22 mL, 0.44 mmol) are added into the reaction crude obtained from theprevious step. The mixture is purged with argon gas for 10 min. Thendichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (16 mg,0.022 mmol) is added and the mixture is heated at 100° C. for 3.5 hr.The reaction mixture is concentrated to give the crude product.Purification by flash column chromatography affords 27 mg of the titleproduct.

Compound 84 to 95, Compound 97 to 148, Compound 163 to 164 and Compound183 in Table 1 are synthesized according to the procedures for Example5, substituting Intermediate B5 and/or Intermediate A4 with eithercommercially available reagents or the appropriate intermediates listedbelow.

Bromide for Cpd No Boronic ester Bromide 84 Commercial Intermediate A785 Commercial Intermediate A8 86 Commercial Intermediate A3 87Commercial Intermediate A4 88 Commercial Intermediate A7 89 CommercialIntermediate A8 90 Commercial Intermediate A4 91 Commercial IntermediateA7 92 Intermediate B5 Intermediate A8 93 Commercial Intermediate A8 94Commercial Intermediate A3 95 Commercial Intermediate A3 97 CommercialIntermediate A4 98 Commercial Intermediate A4 99 Commercial IntermediateA3 100 Commercial Intermediate A3 101 Commercial Intermediate A4 102Intermediate B15 Intermediate A2 103 Commercial Intermediate A4 104Intermediate B1 Intermediate A3 105 Intermediate B1 Intermediate A4 106Intermediate B4 Intermediate A4 107 Intermediate B6 Intermediate A4 108Intermediate B6 Intermediate A3 109 Intermediate B2 Intermediate A4 110Commercial Intermediate A4 111 Intermediate B6 Intermediate A7 112Intermediate B6 Intermediate A8 113 Intermediate B3 Intermediate A4 114Commercial Intermediate A8 115 Commercial Intermediate A3 116 CommercialIntermediate A4 117 Commercial Intermediate A3 118 CommercialIntermediate A4 119 Commercial Intermediate A4 120 CommercialIntermediate A3 121 Commercial Intermediate A4 122 CommercialIntermediate A3 123 Commercial Intermediate A4 124 CommercialIntermediate A4 125 Commercial Intermediate A3 126 CommercialIntermediate A4 127 Commercial Intermediate A4 128 CommercialIntermediate A11 129 Commercial Intermediate A12 130 CommercialIntermediate A3 131 Intermediate B7 Intermediate A3 132 Intermediate B7Intermediate A11 133 Intermediate B7 Intermediate A12 134 IntermediateB8 Intermediate A4 135 Intermediate B8 Intermediate A11 136 IntermediateB8 Intermediate A12 137 Intermediate B9 Intermediate A4 138 IntermediateB9 Intermediate A3 139 Intermediate B10 Intermediate A4 140 IntermediateB10 Intermediate A3 141 Intermediate B11 Intermediate A4 142Intermediate B11 Intermediate A3 143 Intermediate B11 Intermediate A11144 Intermediate B11 Intermediate A12 145 Intermediate B12 IntermediateA4 146 Intermediate B12 Intermediate A3 147 Intermediate B12Intermediate A11 148 Intermediate B13 Intermediate A4 163 IntermediateB15 Intermediate A3 164 Intermediate B15 Intermediate A4 183 CommercialIntermediate A3

Example 6: Synthesis of8-(4-fluoro-1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ylamine,Enantiomer II (Cpd 149, Table 1)

Intermediate B5 and Intermediate A10 are converted to[8-(4-fluoro-1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-carbamicacid tert-butyl ester according to the procedures for Example 5 in Step1 and Step 2.

[8-(4-Fluoro-1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-carbamicacid tert-butyl ester (72 mg, 0.18 mmol) is dissolved in DCM (5.0 mL)and trifluoroacetic acid (0.3 mL) is added. The mixture is stirred for 3hr and saturated aqueous NaHCO₃ (5 mL) is added along with 10 mL ofwater. The mixture is stirred for 10 min and the aqueous layer isseparated and extracted with DCM (3×15 mL) and EtOAc (3×15 mL). All theorganic layers are combined and concentrated to give the crude product.Purification by flash column chromatography affords 25 mg of the titleproduct.

Example 7: Synthesis ofN-[8-(4-fluoro-1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-propionamide,Enantiomer II (Cpd 150, Table 1)

Compound 149 is prepared according to the procedures for Example 6 inStep 1 to Step 3.

Compound 149 (51 mg, 0.17 mmol), propionic acid (0.019 mL) and triethylamine (0.071 mL, 0.51 mmol) are mixed in acetonitrile (2.0 mL). ThenO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (66mg, 0.21 mmol) is added and the mixture is stirred for 3 hr. The solventis removed to give the crude product. Purification by flash columnchromatography affords 32 mg of the title product.

Compounds 151 to 156 in Table 1 are synthesized according to theprocedures for Example 7, substituting with either commerciallyavailable reagents or the appropriate intermediates listed below.

Bromide for Cpd No Boronic ester Bromide 151 Commercial Intermediate A9152 Commercial Intermediate A10 153 Commercial Intermediate A10 154Commercial Intermediate A10 155 Commercial Intermediate A9 156Commercial Intermediate A9

Example 8: Synthesis of ethanesulfonic acid[8-(1-oxo-indan-5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide,Enantiomer II (Cpd 157, Table 1)

5-Bromo-indan-1-one and Intermediate A10 are converted to5-(4-amino-3,4-dihydro-1H-pyrano[4,3-c]pyridin-8-yl)-indan-1-oneaccording to the procedures for Example 6 in Step 1 to Step 3.

5-(4-Amino-3,4-dihydro-1H-pyrano[4,3-c]pyridin-8-yl)-indan-1-one (31 mg,0.11 mmol) is dissolved in DCM (1.0 mL) and ethanesulfonyl chloride(0.012 mL, 0.12 mmol) is added followed by the addition of triethylamine (0.031 mL, 0.22 mmol). The mixture is stirred for 1 hr and DCM (20mL) is added along with saturated aqueous NaHCO₃ solution (10 mL) andwater (15 mL). The mixture is stirred for 10 min and the aqueous layeris separated and extracted with DCM (2×20 mL). All the organic layersare combined and concentrated to give the crude product. Purification byflash column chromatography affords 17 mg of the title product.

Compound 158 and 159 in Table 1 are synthesized according to theprocedures for Example 8, substituting with either commerciallyavailable reagents or the appropriate intermediates listed below.

Bromide for Cpd No Boronic ester Bromide 158 Commercial Intermediate A10159 Commercial Intermediate A9

Example 9: Syntheses of6-(4-hydroxy-3,4-dihydro-1H-pyrano[3,4-c]pyridin-5-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-CarboxylicAcid Amide and its Enantiomers (Cpd 160, 161 and 162, Table 1)

Intermediate B15 and Intermediate A13 are coupled to give6-(4-oxo-3,4-dihydro-1H-pyrano[3,4-c]pyridin-5-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid amide according to the procedures for Example 5 in Step 1 and Step2.

6-(4-Oxo-3,4-dihydro-1H-pyrano[3,4-c]pyridin-5-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid amide (110 mg, 0.33 mmol) is suspended in MeOH (26 mL) and sodiumborohydride (250 mg, 6.6 mmol) is added. The mixture is stirred for 2 hrand saturated aqueous NH₄Cl solution (40 mL) is added slowly. Themixture is extracted with EtOAc (4×125 mL) and the combined organiclayers are dried and concentrated to give the crude product.Purification by flash column chromatography affords 86 mg of the racemictilted product.

Chiral separation of the racemic6-(4-hydroxy-3,4-dihydro-1H-pyrano[3,4-c]pyridin-5-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid amide (81 mg) using Supercritical Fluid Chromatography affords 26mg of Enantiomer I (Compound 161, 2.37 min) and 27 mg of Enantiomer II(Compound 162, 3.24 min). The retention times are measured using thefollowing conditions: LUX 5u Cellulose 3 Analytical column, Mobile phase25% (1:1:1 MeOH:iPA:EtOH+1% DEA):CO2 @ 3 mL/min, 40° C., 200 bars.

Compounds 165 to 168 in Table 1 are synthesized according to theprocedures for Example 9, substituting Intermediate B15 withcommercially available reagents.

The chiral separation of racemic material using Supercritical FluidChromatography affords Compound 165 (retention time, 1.76 min) and 166(retention time, 2.42 min). The retention times are measured using thefollowing conditions: LUX 5u Cellulose 1 Analytical column, Mobile phase20% (1:1:1 MeOH:EtOH:IPA):CO2 @ 3 mL/min, 200 bar, 40° C.

The chiral separation of racemic material using Supercritical FluidChromatography affords Compound 167 (retention time, 4.21 min) andCompound 168 (retention time, 8.57). The retention times are measuredusing the following conditions: LUX 5u Cellulose 4 Analytical column,Mobile phase 20% (1:1:1 MeOH:EtOH:IPA):CO2 @ 3 mL/min, 200 bar, 40° C.

Example 10: Syntheses of Both Enantiomers of6-(4-hydroxy-4-methyl-3,4-dihydro-1H-pyrano[4,3-c]pyridin-8-yl)-1-methyl-1H-indazole-4-carbonitrile(Cpd 173 and 174, Table 1)

Intermediate B4 and Intermediate A5 are coupled to give racemic6-(4-hydroxy-4-methyl-3,4-dihydro-1H-pyrano[4,3-c]pyridin-8-yl)-1-methyl-1H-indazole-4-carbonitrileaccording to the procedures for Example 5 in Step 1 and 2.

Chiral separation of the racemic6-(4-hydroxy-4-methyl-3,4-dihydro-1H-pyrano[4,3-c]pyridin-8-yl)-1-methyl-1H-indazole-4-carbonitrile(126 mg) using Supercritical Fluid Chromatography affords 43 mg ofEnantiomer I (Compound 173, 2.84 min) and 42 mg of Enantiomer II(Compound 174, 3.75 min). The retention times are measured using thefollowing conditions: Regis RegisPack Analytical column, Mobile phase12% (1:1:1 MeOH:iPA:EtOH):CO2 @ 3 mL/min, 40° C., 200 bars.

Compound 169 to 172 and Compound 175 to 178 in Table 1 are synthesizedaccording to the procedures for Example 10, substituting Intermediate B4with either commercially available reagents or the appropriateintermediates listed below.

Bromide for Cpd No Boronic ester Bromide 169 commercial Intermediate A5170 commercial Intermediate A5 171 Intermediate B14 Intermediate A5 172Intermediate B14 Intermediate A5 175 Intermediate B5 Intermediate A5 176Intermediate B5 Intermediate A5 177 Intermediate B3 Intermediate A5 178Intermediate B3 Intermediate A5

The chiral separation of racemic material using Supercritical FluidChromatography affords Compound 169 (retention time, 2.67 min) and 170(retention time, 3.49 min). The retention times are measured using thefollowing conditions: Regis RegisPack Analytical column, Mobile phase20% (1:1:1 MeOH:EtOH:IPA):CO2 @ 3 mL/min, 200 bar, 40° C.

The chiral separation of racemic material using Supercritical FluidChromatography affords Compound 171 (retention time, 9.28 min) and 172(retention time, 13.54 min). The retention times are measured using thefollowing conditions: ES Chromega CC4 analytical column, Mobile phase20% (1:1:1 MeOH:EtOH:IPA):CO2 @ 3 mL/min, 200 bar, 40° C.

The chiral separation of racemic material using Supercritical FluidChromatography affords Compound 176 (retention time, 3.83 min) and 175(retention time, 5.53 min). The retention times are measured using thefollowing conditions: Regis RegisPack Analytical column, Mobile phase10% (1:1:1 MeOH:EtOH:IPA):CO2 @ 3 mL/min, 200 bar, 40° C.

The chiral separation of racemic material using Supercritical FluidChromatography affords Compound 177 (retention time, 4.79 min) and 178(retention time, 7.93 min). The retention times are measured using thefollowing conditions: ES Chromega CC4 analytical column, Mobile phase20% (1:1:1 MeOH:EtOH:IPA):CO2 @ 3 mL/min, 200 bar, 40° C.

Example 11: Syntheses of Both Enantiomers of4-methyl-5-(1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[3,4-c]pyridin-4-ol(Cpd 179 and 180, Table 1)

Intermediate A13 is coupled with (1-methylindazol-6-yl)boronic acid togive 5-(1-methyl-1H-indazol-6-yl)-1H-pyrano[3,4-c]pyridin-4-oneaccording to the procedure for Example 1 in Step 1.

To a solution of5-(1-methyl-1H-indazol-6-yl)-1H-pyrano[3,4-c]pyridin-4-one (110 mg, 0.39mmol) in THF (5.0 mL) cooled at 0° C. is added 3.0 M methyl magnesiumbromide solution (0.26 mL, 0.79 mmol). The reaction is stirred for 2 hrand allowed to warm to room temperature. Water is added and the mixtureis extracted with EtAOc. The organic layer is separated and concentratedto give the crude product. Purification by flash column chromatographyaffords 30 mg of the racemic4-methyl-5-(1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[3,4-c]pyridin-4-ol.

Chiral separation of the racemic4-methyl-5-(1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[3,4-c]pyridin-4-ol(30 mg) using Supercritical Fluid Chromatography affords 9 mg ofEnantiomer I (Compound 179, 2.70 min) and 8 mg of Enantiomer II(Compound 180, 4.47 min). The retention times are measured using thefollowing conditions: LUX 5u Cellulose 3 Analytical column, Mobile phase5% (1:1:1 MeOH:EtOH:IPA):CO2 @ 3 mL/min, 40° C., 200 bars.

Example 12: Synthesis of2-(4-hydroxy-3,4-dihydro-1H-pyrano[4,3-c]pyridin-8-yl)-6,7-dihydro-[1]pyrindin-5-one,Enantiomer I (Cpd 181, Table 1)

Intermediate A3 (40 mg, 0.17 mmol), bis(pinacolato)diboron (66 mg, 0.26mmol), potassium acetate (68 mg, 0.70 mmol) and[1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (13 mg,0.017 mmol) are mixed in 1,4-dioxane (2.0 mL). The reaction mixture isheated at 120° C. under Argon for 18 hr. After the mixture is cooleddown to room temperature, it is used in the next step without workup orpurification.

2-Bromo-6,7-dihydro-[1]pyrindin-5-one (31 mg, 0.15 mmol), 2.0 M Na₂CO₃aqueous solution (0.22 mL, 0.44 mmol),[1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (5.3 mg,0.007 mmol) and 1.0 mL of 1,4-dioxane are added into the reaction crudeobtained from the previous step. The mixture is then heated at 100° C.under Argon for 4 hr. After cooling down to room temperature, themixture is concentrated and the residue is diluted with EtOAc. Theorganic layer is washed with water, brine, dried over Na₂SO₄ andconcentrated to give the crude product. Purification by flash columnchromatography affords 18 mg of the title product.

Compound 182 in Table 1 is synthesized according to the procedures forExample 12, substituting 2-bromo-6,7-dihydro-[1]pyrindin-5-one withcommercially available reagent.

Example 13: Synthesis of Ethanesulfonic Acid[8-(1-hydroxy-indan-5-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amide,Mixture of Diastereomers (Cpd 184, Table 1)

Compound 157 (18 mg, 0.048 mmol) is dissolved in MeOH (1.0 mL) andsodium borohydride (10 mg, 0.26 mmol) is added. The mixture is stirredfor 1 hr and the solvent is removed. Then saturated aqueous NH₄Clsolution (5.0 mL) is added along with water (5.0 mL) and EtOAc (15 mL).The mixture is stirred for 10 min and the aqueous layer is separated andextracted with EtOAc (2×10 mL). The organic layers are combined andconcentrated to give the crude product. Purification by flash columnchromatography affords 15 mg of the title product.

Example 14: Synthesis ofdimethyl-[8-(1-methyl-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl]-amine,Enantiomer II (Cpd 185, Table 1)

To a solution of Compound 71 (31 mg, 0.11 mmol) in MeOH (1.0 mL) areadded 37% formaldehyde aqueous solution (33 mg, 1.1 mmol) and sodiumcyanoborohydride (35 mg, 0.55 mmol). The reaction mixture is stirred atroom temperature for 3 hr and the solvent is removed to give the crudeproduct. Purification by flash column chromatography affords 10 mg ofthe title product.

Example 15: Synthesis of4-(4-hydroxy-3,4-dihydro-1H-pyrano[4,3-c]pyridin-8-yl)-cyclohex-3-enecarbonitrile,Enantiomer I (Cpd 186, Table 1)

Intermediate A3 is converted to8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-olaccording to the procedure for Step 1 in Example 12.

Intermediate B16 (94 mg, 0.37 mmol), 3.0 M Na₂CO₃ aqueous solution (0.1mL, 0.30 mmol) and[1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (27 mg,0.037 mmol) are added into the crude8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol(0.37 mmol) obtained from the previous step. The mixture is heated at90° C. for 18 hr before it is concentrated to give the crude product.Purification by flash column chromatography affords 30 mg of the titledproduct.

Compound 187, 189 and 192 in Table 1 are synthesized according to theprocedures for Example 15, substituting Intermediate A3 and IntermediateB16 with the appropriate intermediates listed below.

Bromide for Cpd No Boronic ester Triflate 187 Intermediate A4Intermediate B17 189 Intermediate A3 Intermediate B17 192 IntermediateA4 Intermdeiate B16

Example 16: Syntheses of Diastereomers of8-(1-methyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol(Cpd 190 and 191, Table 1)

To the solution of Compound 187 (50 mg, 0.18 mmol) in EtOH (3.0 mL) areadded ammonium formate (50 mg, 0.79 mmol) and 10% Pd on activated carbon(28 mg, 0.026 mmol). The mixture is stirred at 90° C. for 30 hrs beforeit is filtered and concentrated. The residue is dissolved in EtOAc (15mL) and it is washed with water (2×10 mL). The organic layer is driedand concentrated to give the crude products. Purification by flashcolumn chromatography affords 8 mg of Compound 190 and 7 mg of Compound191.

LCMS Data for Compounds in Table 1 are shown in Table 2, which aremeasured using the methods set forth in the following Table.

LC Methods Mobile Gradient Flow Method Mobile Phase A Phase B Time (min)% A % B (mL/min.) Column A 0.1% Formic 0.1% 0 90.0 10.0 0.5 Thermo Acidin Water Formic 0.5 90.0 10.0 Scientific, Acid in 1.5 1.0 99.0 AquasilC18, Acetonitrile 2.5 1.0 99.0 50 × 2.1 mm, 3.3 90.0 10.0 5μ 4.0 90.010.0 B 0.1% Formic 0.1% 0 95 5 0.8 BEH Acid in Water Formic 1.0 5 95 2.5× 50 mm Acid in 1.3 5 95 C18, 1.7 μm Acetonitrile 1.4 95 5 particle 1.795 5 diameter C 5% Acetonitrile 100% 0 90.0 10.0 0.8 BEH in 2.5 mMAcetonitrile 1.19 5.0 95.0 2.1 × 50 mm aqueous 1.77 5.0 95.0 C18, 1.7 μmAmmonium 1.78 90.0 10.0 particle Bicarbonate diameter D 5% Acetonitrile100% 90% A to 100% B in 1.19 minutes 0.8 BEH in 2.5 mM Acetonitrile holdat 100% B to 1.70 minutes 2.1 × 50 mm aqueous C18, 1.7 um Ammoniumparticle Bicarbonate diameter E 95% Water 0.05% 90% A to 100% B in 1.19minutes 0.8 CSH 5% Acetonitrile Formic hold at 100% B to 1.70 minutes2.1 × 50 mm 0.05% Formic Acid in C18, 1.7 um Acid Acetonitrile particlediameter F 95% Water 0.05% 95% A to 100% B in 3.65 minutes, 0.6 HSS T35% Acetonitrile Formic hold at 100% B to 4.95 minutes 2.1 × 100 mm 0.05%Formic Acid in C18, 1.8 um Acid Acetonitrile particle diameter

TABLE 2 Cpd Mass Retention LC No. Found Time (min) Method 1 296.7 0.28 A2 296.7 0.27 A 3 227.1 0.45 B 4 252.6 1.72 A 5 227.1 0.46 B 6 252.5 1.72A 7 286.1 0.56 B 8 292.9 1.24 A 9 291.3 2.69 A 10 281.7 0.97 A 11 281.10.49 B 12 281.1 0.43 B 13 281.1 0.49 B 14 282.7 0.97 A 15 299.1 0.54 B16 307.1 0.69 B 17 307.1 0.78 B 18 299.1 0.55 B 19 299.1 0.55 B 20 285.11.19 A 21 267.2 1.19 A 22 278.8 1.23 A 23 282.1 1.19 A 24 268.3 1.2 A 25286.2 1.2 A 26 260.2 1.19 A 27 268.3 1.2 A 28 300.2 1.19 A 29 281.7 1.2A 30 279.2 1.2 A 31 267.2 1.19 A 32 232.3 1.19 A 33 285.1 1.19 A 34267.2 1.2 A 35 279.3 1.2 A 36 282.2 1.19 A 37 268.3 1.2 A 38 286.2 1.2 A39 260.2 1.2 A 40 268.3 1.21 A 41 246.2 1.18 A 42 299.1 0.6 B 43 299.10.5 B 44 281.6 1.2 A 45 279.2 1.2 A 46 257.7 1.21 A 47 267.7 1.21 A 48267.2 1.19 A 49 268.1 0.47 B 50 281.1 0.46 B 51 296.1 0.45 B 52 282.10.39 B 53 268.1 0.47 B 54 296.1 0.45 B 55 299.1 0.56 B 56 323.1 0.52 B57 336.2 0.39 B 58 351.2 0.49 B 59 337.1 0.44 B 60 337.2 0.51 B 61 336.20.5 B 62 336.2 0.55 B 63 387.1 0.53 B 64 373.1 0.48 B 65 373.1 0.55 B 66372.1 0.59 B 67 373.2 0.49 C 68 391.3 1.01 A 69 373.3 0.96 A 70 294.10.46 B 71 281.3 1.27 A 72 336.2 0.47 B 73 336.2 0.47 B 74 323.3 1.3 A 75349.3 1.3 A 76 336.7 1.33 A 77 350.2 0.59 B 78 387.2 0.65 E 79 386.82.07 A 80 358.1 0.5 B 81 358.1 0.5 B 82 372.1 0.51 B 83 372.1 0.57 B 84323.3 1.14 A 85 323.3 1.14 A 86 281.7 1.29 A 87 281.7 1.27 A 88 307.70.21 A 89 307.1 0.36 B 90 282.1 0.5 B 91 309.2 0.38 D 92 326.3 1 A 93308.1 0.4 B 94 282.1 0.5 B 95 282.1 0.33 B 96 299.1 0.52 B 97 282.1 0.33B 98 268.6 0.27 A 99 267.7 0.23 A 100 268.6 0.27 A 101 267.7 0.27 A 102326.1 0.38 B 103 281.7 1.69 A 104 321.7 1.17 A 105 321.1 0.4 B 106 307.20.53 E 107 299.1 0.45 B 108 299.1 0.45 B 109 310.1 0.45 B 110 295.1 0.49B 111 326.3 1.27 A 112 326.3 1.26 A 113 306.1 0.58 B 114 308.1 0.63 B115 295.1 0.5 B 116 295.1 0.5 B 117 295.1 0.5 B 118 295.1 0.5 B 119296.1 0.38 B 120 296.7 1.18 A 121 296.7 1.17 A 122 297.1 0.46 B 123297.1 0.45 B 124 310.1 0.41 B 125 296.1 1.19 A 126 295.6 1.25 A 127302.1 0.97 A 128 357.3 1.02 A 129 393.2 1 A 130 302.1 0.97 A 131 300.30.96 A 132 355.2 0.95 A 133 391.3 0.96 A 134 300.2 0.96 A 135 355.2 0.95A 136 391.2 0.96 A 137 314.3 0.95 A 138 314.3 0.96 A 139 314.3 0.95 A140 314.3 0.96 A 141 320.2 1 A 142 320.2 1 A 143 375.4 1.05 A 144 411.31.03 A 145 313.1 0.36 C 146 313.1 0.36 C 147 368.3 0.96 A 148 334.3 1 A149 298.1 0.48 B 150 354.1 0.59 B 151 322.1 0.46 B 152 322.1 0.46 B 153380.7 1.17 A 154 336.1 0.45 B 155 336.2 0.52 B 156 337.1 0.63 B 157372.1 0.55 B 158 387.2 1.28 A 159 373.1 0.68 B 160 326.7 1.64 A 161326.1 0.38 B 162 326.1 0.38 B 163 327.4 1.6 A 164 327.4 1.6 A 165 281.10.45 B 166 281.6 1.29 A 167 278.1 0.57 B 168 278.1 0.8 B 169 296.2 1.26A 170 296.2 1.26 A 171 313.1 0.59 B 172 313.1 0.6 B 173 320.1 0.58 B 174320.1 0.58 B 175 313.1 0.59 B 176 313.1 0.59 B 177 320.1 0.64 B 178320.1 0.64 B 179 295.1 0.46 B 180 295.1 0.46 B 181 283.2 1.16 A 182297.1 0.58 B 183 281.7 1.12 A 184 374.1 0.51 B 185 309.3 1.26 A 186256.1 0.42 B 187 283.7 1.12 A 188 283.0 0.30 E 189 284.4 0.35 E 190286.3 0.91 F 191 286.3 0.83 F 192 257.5 0.26 E 193 355.2 0.63 C 194375.2 0.73 C 195 391.2 0.66 C 196 411.2 0.76 C 197 309.3 0.52 C 198309.3 0.52 C 199 320.4 1.92 A 200 320.4 1.92 A

Assessment of Biological Activity Inhibition of Aldosterone Synthase

The compounds of the invention may be evaluated for aldosterone synthaseinhibition by the following assay:

The aldosterone synthase inhibition assay employs cynomolgus adrenalgland mitochondria as the source of aldosterone synthase (CYP11B2).Mitochondria are prepared from frozen cynomolgus monkey adrenal glandsaccording to Method A described in by J. D. McGarry et al. (Biochem. J.,1983, 214, 21-28), with a final resuspension in the AT buffer describedin R. Yamaguchi et al. (Cell Death and Differentiation, 2007, 14,616-624), frozen as aliquots in liquid nitrogen and stored at −80° C.until use.

Assays are performed in 96-well format in a final volume of 60 μL/well,containing 100 mM potassium phosphate, pH 7.4, 1% (v/v) DMSO, andadditionally, 2 μM of corticosterone and 6 mg of mitochondrial protein.Reactions are started by the addition of NADPH to 1 mM and allowed toproceed for 60-90 minutes at 37° C. Reactions are terminated by theaddition of 60 of acetonitrile. One hundred microliters are thentransferred to a glass filter plate and centrifuged at 570×g for 5minutes and the filtrate is collected. Reaction product aldosterone isquantified by mass spectrometry. To determine the assay blank value (0%activity), NADPH is omitted from some reactions.

Dose dependent inhibition is quantified by the inclusion of compound atvarious concentrations. Maximum activity (100%) is defined by reactionscontaining NADPH, but without compound. Activities at each concentrationare expressed as a percentage of the maximum activity (y-axis) andplotted against concentration of compound (x-axis) and the concentrationcorresponding to 50% activity (IC50) determined using the XLFitcurve-fitting program using a 4-parameter logistic model.

Representative compounds of the present invention were tested foractivity in the above assay. Preferred compounds have an IC₅₀<1,000 nMand more preferred compounds have an IC₅₀<100 nM in this assay. Asexamples, data for representative compounds from Table 1 are shown inTable 3.

TABLE 3 Cpd No. IC₅₀ (nM) 1 28.9 2 100.7 3 483.7 4 42 5 55 6 9.8 7 6.1 83700 9 5.7 10 114.9 11 689.6 12 21 13 81 14 15.7 15 7.8 16 12.5 17 8 1820.1 19 153 20 681.2 21 194.9 22 64.1 23 194.9 24 480 25 158.7 26 150027 1300 28 333.2 29 48.6 30 54 31 159.7 32 2700 33 40.5 34 17.3 35 9.736 17.5 37 94.4 38 12 39 437.5 40 185.7 41 1000 42 367.4 43 22 44 8.5 455.8 46 301.7 47 50 48 17.4 49 55.7 50 1200 51 24.2 52 64.1 53 807.8 54148.7 55 7.6 56 85.8 57 219.1 58 129.6 59 178.9 60 75.5 61 36.2 62 138.663 85.2 64 610.8 65 36.1 66 1000 67 109.7 68 15.9 69 84.6 70 166.1 7122.2 72 2300 73 34.6 74 25.6 75 26.4 76 17.9 77 32.6 78 2800 79 652.7 802100 81 28.5 82 215.4 83 31.3 84 255 85 90.9 86 494.4 87 123.3 88 128.589 73 90 8.5 91 220.5 92 11.5 93 271.3 94 10.1 95 766.4 96 8.1 97 204.998 1300 99 5000 100 2300 101 224.9 102 64.9 103 10 104 81 105 51.1 106599 107 79.9 108 771.4 109 544.4 110 13 111 114 112 40.9 113 14.5 11418.8 115 579.7 116 26.3 117 103.2 118 12.5 119 960 120 789.9 121 95 122193.6 123 16.3 124 1006.8 125 22.8 126 14 127 6.7 128 11.2 129 45.9 130238.1 131 1469.7 132 518.1 133 1469.7 134 252.6 135 340.7 136 10000 1371873.5 138 1555.6 139 2800 140 12000 141 339.4 142 117.7 143 27.9 144470.1 145 737.7 146 9726.3 147 1688.2 148 83.7 149 17.3 150 17.4 1514875.5 152 50.2 153 70 154 26.3 155 3800 156 311.8 157 46 158 13 159797.5 160 51.1 161 35.3 162 71.4 163 44.3 164 41.5 165 223.6 166 36.5167 155.6 168 40.5 169 13.9 170 7.8 171 19.1 172 10.2 173 340 174 4400175 21.6 176 13.4 177 42.8 178 15 179 38.9 180 281.4 181 149.7 182 496183 52 184 124.1 185 18 186 67 187 12.9 188 21 189 67 190 340 191 48 19214 193 38 194 38 195 140 196 330 197 18 198 19 199 22 200 279

Methods of Therapeutic Use

In accordance with the invention, there are provided novel methods ofusing the compounds of formula (I). The compounds disclosed hereineffectively inhibit aldosterone synthase. The inhibition of aldosteronesynthase is an attractive means for preventing and treating a variety ofdiseases or conditions that can be alleviated by lowering levels ofaldosterone. Thus, the compounds are useful for the treatment ofdiseases and conditions as described in the Background section,including the following conditions and diseases:

Diabetic kidney disease including diabetic nephropathy;

Non-diabetic kidney disease including glomerulosclerosis,glomerulonephritis, IGA nephropathy, nephritic syndrome and focalsegmental glomerulosclerosis (FSGS);

Cardiovascular diseases including hypertension, pulmonary arterialhypertension, Conn's syndrome, systolic heart failure, diastolic heartfailure, left ventricular dysfunction, left ventricular stiffness andfibrosis, left ventricular filing abnormalities, arterial stiffness,atherosclerosis and cardiovascular morbidity associated with primary orsecondary hyperaldosteronism;

Adrenal hyperplasia and primary and secondary hyperaldosteronism.

These disorders have been well characterized in man, but also exist witha similar etiology in other mammals, and can be treated bypharmaceutical compositions of the present invention.

For therapeutic use, the compounds of the invention may be administeredvia a pharmaceutical composition in any conventional pharmaceuticaldosage form in any conventional manner. Conventional dosage formstypically include a pharmaceutically acceptable carrier suitable to theparticular dosage form selected. Routes of administration include, butare not limited to, intravenously, intramuscularly, subcutaneously,intrasynovially, by infusion, sublingually, transdermally, orally,topically or by inhalation. The preferred modes of administration areoral and intravenous.

The compounds of this invention may be administered alone or incombination with adjuvants that enhance stability of the inhibitors,facilitate administration of pharmaceutical compositions containing themin certain embodiments, provide increased dissolution or dispersion,increase inhibitory activity, provide adjunct therapy, and the like,including other active ingredients. In one embodiment, for example,multiple compounds of the present invention can be administered.Advantageously, such combination therapies utilize lower dosages of theconventional therapeutics, thus avoiding possible toxicity and adverseside effects incurred when those agents are used as monotherapies.Compounds of the invention may be physically combined with theconventional therapeutics or other adjuvants into a singlepharmaceutical composition. Advantageously, the compounds may then beadministered together in a single dosage form. In some embodiments, thepharmaceutical compositions comprising such combinations of compoundscontain at least about 5%, but more preferably at least about 20%, of acompound of formula (I) (w/w) or a combination thereof. The optimumpercentage (w/w) of a compound of the invention may vary and is withinthe purview of those skilled in the art. Alternatively, the compounds ofthe present invention and the conventional therapeutics or otheradjuvants may be administered separately (either serially or inparallel). Separate dosing allows for greater flexibility in the dosingregime.

As mentioned above, dosage forms of the compounds of this invention mayinclude pharmaceutically acceptable carriers and adjuvants known tothose of ordinary skill in the art and suitable to the dosage form.These carriers and adjuvants include, for example, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, buffer substances,water, salts or electrolytes and cellulose-based substances. Preferreddosage forms include tablet, capsule, caplet, liquid, solution,suspension, emulsion, lozenges, syrup, reconstitutable powder, granule,suppository and transdermal patch. Methods for preparing such dosageforms are known (see, for example, H. C. Ansel and N. G. Popovish,Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea andFebiger (1990)). Dosage levels and requirements for the compounds of thepresent invention may be selected by those of ordinary skill in the artfrom available methods and techniques suitable for a particular patient.In some embodiments, dosage levels range from about 1-1000 mg/dose for a70 kg patient. Although one dose per day may be sufficient, up to 5doses per day may be given. For oral doses, up to 2000 mg/day may berequired. As the skilled artisan will appreciate, lower or higher dosesmay be required depending on particular factors. For instance, specificdosage and treatment regimens will depend on factors such as thepatient's general health profile, the severity and course of thepatient's disorder or disposition thereto, and the judgment of thetreating physician.

1. A compound of formula IA or IB

wherein: A is selected from the group consisting of benzoimidazolyl, benzo[d]isoxazolyl, benzooxazolyl, benzothiazolyl, benzotriazolyl, chromanyl, chromenyl, cyclohexen-1-yl, 2,3-dihydro-benzo[1,4]dioxinyl, 2,3-dihydro-5H-benzo[e][1,4]dioxepinyl, 3,4-dihydro-2H-benzo[1,4]dioxepinyl, 3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-onyl, 2,3-dihydro-benzofuranyl, 4,5-dihydro-1H-indazolyl, 1,3-dihydroindol-2-onyl, 1,3-dihydro-isoindolyl, 3,4-dihydro-2H-isoquinolin-1-onyl, 3,4-dihydro-2H-naphthalen-1-onyl, 3,4-dihydro-2H-[1,8]napthyridinyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, 6,7-dihydro-[1]pyrindin-5-onyl, 3,4-dihydro-1H-quinolin-2-onyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, indanyl, indazolyl, indolyl, isochromanyl, isoquinolinyl, phenyl, pyrazolyl, pyrrolo[2,3-b]pyridinyl, quinolinyl, 1,3,4,5-tetrahydro-benzo[c]oxepinyl, 4, 5, 6, 7-tetrahydroindazolyl, thiazolyl and [1,2,4]triazolo[4,3-a]pyridinyl; wherein A is optionally substituted with one to three groups selected from C₁₋₆alkyl, C₃₋₅cycloalkyl, —OH, oxo, C₁₋₆alkoxy, halogen, —CF₃, —CN, —C(O)C₁₋₃alkyl and —C(O)NH₂; R¹ is selected from H and —C₁₋₃alkyl; R² is selected from —OH, —CN, —NH₂, —N(C₁₋₃alkyl)₂, —NHC(O)C₁₋₃alkyl, —NHC(O) C₃₋₅ cycloalkyl, —NHSO₂C₁₋₃alkyl and —NHC(O)CH₂C(CH₃)₂—OH; R³ is H; R⁴ is H; or R³ and R⁴ together form a spiro cyclopropyl group; R⁵ is H or —C₁₋₃alkyl; and R⁶ is —OH; or a salt thereof.
 2. The compound of the formula IA according to claim 1, or a salt thereof.
 3. The compounds of the formula IB according to claim 1, wherein A is selected from the group consisting of benzo[d]isoxazol-5-yl, benzotriazol-5-yl, chromen-6- or -7-yl, cyclohexen-1-yl, 4,5-dihydro-1H-indazol-6-yl, 3,4-dihydro-2H-[1,8]napthyridin-6-yl, imidazo[1,5-a]pyridine-6-yl, indan-5-yl, indazol-5- or -6-yl, isochroman-7-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, 2,3-dihydro-5H-benzo[1,4]dioxepin-7-yl, 3,4-dihydro-2H-naphthalen-1-on-6- or -7-yl, chroman-6- or -7-yl, 1,3,4,5-tetrahydro-benzo[c]oxepin-8-yl and 4, 5, 6, 7-tetrahydroindazol-6-yl; R⁵ is H or —CH₃; and R⁶ is OH; or a salt thereof.
 4. The compound of the formula IA according to claim 1, wherein A is selected from the group consisting of benzoimidazol-5-yl, benzo[d]isoxazol-5-yl, benzooxazol-5-yl, benzothiazol-5-yl, benzotriazol-5-yl, chroman-6- or -7-yl, chromen-6- or -7-yl, cyclohexen-1-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, 2,3-dihydro-5H-benzo[e][1,4]dioxepin-7-yl, 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, 4,5-dihydro-1H-indazol-6-yl, 1,3-dihydroindol-2-on-5-yl, 3,4-dihydro-2H-isoquinolin-1-on-6-yl, 3,4-dihydro-2H-naphthalen-1-on-6- or -7-yl, 3,4-dihydro-2H-[1,8]napthyridin-6-yl, 3,4-dihydro-1H-quinolin-2-on-6-yl, imidazo[1,2-a]pyridine-7-yl, imidazo[1,5-a]pyridine-6-yl, indan-5-yl, indazol-5- or -6-yl, isochroman-7-yl, isoquinolin-6-yl, phenyl, quinolin-3- or -6-yl and 4, 5, 6, 7-tetrahydroindazol-6-yl, indol-5 or 6-yl, 1,3,4,5-tetrahydro-benzo[c]oxepin-8-yl; wherein A is optionally substituted with one to three groups selected from C₁₋₃alkyl, C₃₋₅cycloalkyl, —OH, oxo, C₁₋₃alkoxy, Cl, F, —CF₃, —CN, —C(O)CH₃ and —C(O)NH₂; R¹ is selected from H and —CH₃; and R² is selected from —OH, —CN, —NH₂, —N(CH₃)₂, —NHC(O)C₁₋₃alkyl, —NHC(O)cyclopropyl, —NHSO₂C₁₋₃alkyl and —NHC(O)CH₂C(CH₃)₂—OH; or a salt thereof.
 5. The compound of the formula IA according to claim 1, wherein A is selected from the group consisting of benzo[d]isoxazol-5-yl, benzotriazol-5-yl, chromen-6- or -7-yl, cyclohexen-1-yl, 4,5-dihydro-1H-indazol-6-yl, 3,4-dihydro-2H-[1,8]napthyridin-6-yl, imidazo[1,5-a]pyridine-6-yl, indan-5-yl, indazol-5- or -6-yl, isochroman-7-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, 2,3-dihydro-5H-benzo[e][1,4]dioxepin-7-yl, 3,4-dihydro-2H-naphthalen-1-on-6- or -′7-yl, chroman-6- or -′7-yl, 1,3,4,5-tetrahydro-benzo[c]oxepin-8-yl and 4, 5, 6, 7-tetrahydroindazol-6-yl; wherein A is optionally substituted with one to three groups selected from C₁₋₃alkyl, C₃₋₅cycloalkyl, —OH, oxo, C₁₋₃alkoxy, Cl, F, —CF₃, —CN, —C(O)CH₃ and —C(O)NH₂; and R² is selected from —OH, —CN, —NHC(O)C₁₋₃alkyl, —NHC(O)cyclopropyl, —NHSO₂C₁₋₃alkyl and —NHC(O)CH₂C(CH₃)₂—OH; or a salt thereof.
 6. The compound according to claim 1 selected from the group consisting of

and the pharmaceutically acceptable salts thereof.
 7. The compound according to claim 6 selected from the group consisting of compound numbers 9, 12-18, 29, 34, 36-38, 43-45, 47, 48, 55, 60, 61, 65, 68, 69, 71, 73-77, 81, 83, 85, 89, 90, 92, 94, 96, 102-105, 107, 110, 112-114, 116, 118, 121, 123, 125-129, 131-133, 136, 142, 143, 148-150, 152-154, 157, 158, 160-164, 166, 168-172, 175-179, 183 and 185-199 and the pharmaceutically acceptable salts thereof.
 8. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient or carrier.
 9. A method of treating a disease or disorder that can be alleviated by inhibition of aldosterone synthase selected from diabetic nephropathy, glomerulosclerosis, glomerulonephritis, IGA nephropathy, nephritic syndrome focal segmental glomerulosclerosis (FSGS), hypertension, pulmonary arterial hypertension, Conn's syndrome, systolic heart failure, diastolic heart failure, left ventricular dysfunction, left ventricular stiffness and fibrosis, left ventricular filing abnormalities, arterial stiffness, atherosclerosis and cardiovascular morbidity associated with primary or secondary hyperaldosteronism, adrenal hyperplasia and primary and secondary hyperaldosteronism comprising administering a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to patient in need thereof.
 10. The method according to claim 9, wherein the disease or disorder is selected from diabetic nephropathy, glomerulosclerosis, glomerulonephritis, IGA nephropathy, nephritic syndrome and focal segmental glomerulosclerosis (FSGS).
 11. The method according to claim 9 wherein the disease is diabetic nephropathy.
 12. (canceled) 